SURVEY OF OPHTHALMOLOGY VOLUME 52  NUMBER 1  JANUARY–FEBRUARY 2007

DIAGNOSTIC AND SURGICAL

TECHNIQUES
MARCO ZARBIN AND DAVID CHU, EDITORS

The Clinical Applications of Multifocal

Electroretinography: A Systematic Review
Timothy Y.Y. Lai, MMedSc, MRCSEd, Wai-Man Chan, MRCP, FRCSEd, Ricky Y.K. Lai,
MMedSc, Jasmine W.S. Ngai, MRCSEd, Haitao Li, MD, and Dennis S.C. Lam, MD,
FRCOphth

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong,
People’s Republic of China

Abstract. Multifocal electroretinography (mfERG) is an investigation that can simultaneously

measure multiple electroretinographic responses at different retinal locations by cross-correlation
techniques. mfERG therefore allows topographic mapping of retinal function in the central 40--50 of
the retina. The strength of mfERG lies in its ability to provide objective assessment of the central retinal
function at different retinal areas within a short duration of time. Since the introduction of mfERG in
1992, mfERG has been applied in a large variety of clinical settings. This article reviews the clinical
applications of mfERG based on the currently available evidence. mfERG has been found to be useful
in the assessment of localized retinal dysfunction caused by various acquired or hereditary retinal
disorders. The use of mfERG also enabled clinicians to objectively monitor the treatment outcomes as
the changes in visual functions might not be reflected by subjective methods of assessment. By
changing the stimulus, recording, and analysis parameters, investigation of specific retinal
electrophysiological components can be performed topographically. Further developments and
consolidations of these parameters will likely broaden the use of mfERG in the clinical setting. (Surv
Ophthalmol 52:61--96, 2007. Ó 2007 Elsevier Inc. All rights reserved.)

Key words. electrophysiology  macula  multifocal electroretinography  mfERG  retinal

function

Multifocal electroretinography (mfERG) was de-
veloped by Sutter and Tran in 1992 and has
revolutionized the objective functional assessment
of retinal diseases.290 In contrast with full-field
electroretinography (ERG), which measures the
electrical activity of the entire retina, mfERG allows
simultaneous measurements of multiple retinal
responses at different locations. The use of mfERG
therefore enables topographic mapping of retinal
function in the central 40--50 of the retina. Since
the introduction of mfERG in the clinical setting,
there have been many reports in the literature to
evaluate the use of mfERG in the assessment of
various ophthalmic conditions. This review aims to
summarize the clinical applications of mfERG based
on the currently available evidence.

61
Ó 2007 by Elsevier Inc. 0039-6257/07/$--see front matter
All rights reserved. doi:10.1016/j.survophthal.2006.10.005
62 Surv Ophthalmol 52 (1) January--February 2007
Basics of the Multifocal
Electroretinography
Before looking at the clinical applications of
mfERG, this section will provide a brief overview
on some of the basic concepts of the mfERG. Several
review articles have been published on the funda-
mental and technical aspects of the mfERG and
readers can refer to these publications for further
references.99,105,126,148
RECORDING OF MFERG
mfERG recordings can be performed using
commercially available systems such as the VERIS
system (Electro-Diagnostic Imaging, San Mateo,
CA), the RETIscan system (Roland Consult, Wies-
baden, Germany), and the Metrovision system
(Metrovision, Pérenchies, France). Clinicians
should be aware of the default parameter settings
in each system as these will influence the mfERG
recordings and interpretations.20 A guideline has
been issued by the International Society for Clinical
Electrophysiology of Vision (ISCEV) of which
various researchers have found the settings to be
useful in most situations.185 Prior to recording, the
subject is usually light-adapted for at least 15
minutes with room lights maintained on during
the recording for constant light adaptation. This is
important because alteration of the light adaptation
state and the extent of local bleaching prior or
during mfERG recording can affect the re-
sults.34,143,155 Pre-recording light adaptation may
also help to prevent the circadian rhythm of retinal
responses.90 Patients’ pupils should be fully dilated
to maximize the retinal illumination as changes in
pupil size may result in significant alterations in
mfERG amplitude and latency.74
During mfERG recording, the subject fixates onto
the center of a stimulating monitor, which is most
commonly a cathode ray tube (CRT) monitor. A
liquid crystal display (LCD) monitor or a scanning
laser ophthalmoscope (SLO) can also be used. The
SLO allows direct retinal stimulation and fixation
monitoring simultaneously, although it does not
allow for eye tracking or for moving the stimulus to
compensate for eye movement.24,126,237,238,251,252
Each type of stimulus has its own advantages and
disadvantages in the recordings of offset and non-
linear responses.128 The stimulus is composed of an
array of alternating bright and dark hexagonal
flashes which stimulate the central 40--50 of the
retina. The sizes of the hexagons are scaled
according to the density of retinal response and
therefore the sizes of the hexagons get larger as they
extend peripherally. The number of hexagons used
in the stimulus depends on the spatial resolution
LAI ET AL
required, in which 241 hexagons will provide
greater resolution compared with 61 or 103 hexa-
gons (Fig. 1). With the use of artificial scotomas,
studies have shown that mfERG was able to detect
small retinal lesions if the defect was at least half the
area of a stimulating hexagon.173,184,323 It has been
recommended that the 241-hexagon stimulus
should be used for detecting scotomas of 5 or
smaller184 (Fig. 2). Increasing the number of
hexagons, however, will lengthen the recording
duration and may decrease the signal-to-noise
ratio.91,123 In most clinical settings, 61 or 103
hexagons can provide a good balance between
spatial resolution and length of recording as well
as better signal-to-noise ratio.91 The ISCEV guide-
line recommended the bright and dark hexagons
should have luminance of 100--200 cd/m2 and !1
cd/m2, respectively, in order to provide adequate
contrast.185 This will result in a mean screen
luminance of 50--100 cd/m2 during testing. The
amplifier setting is usually set at a gain of 100,000 to
200,000 with a bandpass filter range of 3--300 Hz or
10--300 Hz. Proper filter bandwidth setting is
essential to remove excessive electrical noise caused
by high amplification and to avoid waveform
distortion, which is particularly important in the
analysis of second-order kernel responses.21,127
Recordings can be carried out monocularly or
binocularly using contact lens or fiber electrodes. We
prefer using a bipolar contact lens electrode (Burian-
Allen electrode, Hansen Laboratories, Coralville, IA)
because larger responses can be obtained with
lower variability and better signal-to-noise ratio
compared with other types of electrodes.126,199
Monocular recording offers the advantage of pre-
venting abnormal recordings due to alternating
fixation in patients with intermittent exotropia.16
Monocular recording also facilitates better fixation
monitoring which is essential because poor fixation
can result in abnormal mfERG responses, especially
when higher number of stimulus elements are
used.44,249 Fixation monitoring can be performed
using direct observation or by various monitoring
instruments such as a refractor/camera system,
a fundus camera or a SLO.24,139,249,252,275 Although
Fig. 1. The mfERG recording stimulus pattern with
different number of hexagonal elements. Left: 61 hexa-
gons; Center: 103 hexagons; Right: 241 hexagons.
APPLICATIONS OF MULTIFOCAL ELECTRORETINOGRAPHY 63

Fig. 2. Different resolutions of mfERG recordings. Left: Trace array (top) and three-dimensional topography (bottom)
of mfERG responses obtained using a 103-hexagon stimulus which showed regular mfERG responses with the normal
blind spot (black arrow). Right: Trace array (top) and three-dimensional topography (bottom) of mfERG responses of the
same patient obtained using a 241-hexagon. The higher number of hexagonal elements improved the resolution of the
mfERG recording. This allowed demonstration of a weaker response at the blind spot (black arrow). A small localized
area of retinal dysfunction (red arrow) corresponding to an area of retinal pigment epithelial atrophy due to previous
intraocular inflammation could also be detected which was not seen with the 103-hexagon stimulus.

these monitoring devices may detect any unwanted
eye movements, it might be difficult to determine
the exact fixating location in patients with central
scotoma. Therefore, eccentric fixation and fixation
instability might account for some of the mfERG
abnormalities. One way to improve the fixation in
patients with central scotoma is by displacing the
fixation cross away from the center of the stimulus
in order to place the non-fixating fovea in the center
of the pattern. This method also allows better
sequential monitoring of macular function and is
particularly useful with the SLO system. With good
fixation monitoring, so as to reject recordings when
a patient is not placing the fovea at the center of the
mfERG pattern or when there is excessive eye
movement, mfERG recordings can provide good
reproducibility especially for the central retinal
responses.6,195,
231,232
Patients’ refractive errors should be corrected
using corrective lens or a refractor/fixation camera
system to provide the optimal image quality.
Although it has been suggested that mild refractive
blurring in normal subjects do not affect the
recordings,225 several studies have demonstrated
that refractive blurring can result in significant
mfERG abnormalities.32,308 This is particularly
64 Surv Ophthalmol 52 (1) January--February 2007
important when using mfERG in the assessment of
functional visual loss because the subject may
deliberately cause refractive blur, which can signifi-
cantly alter the mfERG responses.308
ORIGIN OF MFERG
The recording technique used in mfERG is
known as the pseudorandom m-sequence and it allows
the extraction of a series of responses from in-
dividual retinal locations by cross-correlation. The
response components are called kernels which are
caused by non-linear dynamics of the responses;
readers can refer to review articles by Sutter on the
details of kernel analyses.288,291 The standard
mfERG mainly measures the cone function and
the most commonly analyzed responses are the first-
order and the second-order kernel components;
they will be briefly discussed in this section.
FIRST-ORDER KERNEL COMPONENT OF MFERG
The first-order kernel component of the mfERG
is the largest mfERG response derived and the
waveform is a biphasic wave characterized by an
initial negative deflection followed by a positive
peak. There may also be a second negative de-
flection after the positive peak and these peaks are
labeled as N1, P1, and N2, respectively (Fig. 3). The
first-order kernel component is obtained by adding
all the records following a bright flash and subtract-
ing all the records following a dark flash. Because
the first-order kernel component is the most
common response analyzed in most clinical settings,
Fig. 3. Waveforms of mfERG responses. Top: The
waveform of first-order kernel mfERG response with the
first negative trough N1, followed by a positive peak P1
and a second negative trough N2. Bottom: The waveform of
second-order kernel mfERG response with the first
positive peak P1, followed by a negative trough N1 and
a second positive peak P2.
LAI ET AL
it is the mfERG response referred to in this review
unless otherwise specified.
Although the first-order kernel mfERG response
appears as a biphasic waveform similar to the full-
field ERG waveform, the origins of the waveforms
are rather different. Hood et al compared the
components of mfERG with full-field ERG wave-
forms in normal subjects by altering the background
level, and the interval and intensity of the in-
cremental flash.101 It was shown that there was good
correspondence in the waveform shapes between
the first-order mfERG response and full-field ERG
when the m-sequence stimulus was slowed down by
insertion of seven frames at the background in-
tensity. Slowing of the multifocal stimulus removed
the non-linear components in the mfERG response.
When the frame rate was increased to the standard
flicker rate, the initial N1 component of the mfERG
remained similar to the a-wave of the full-field ERG,
whereas the P1 waveform changed considerably due
to non-linear effects. Therefore, it is likely that both
the N1 wave of the mfERG and the a-wave of the full-
field ERG had the same origin, whereas the P1
mfERG component has some of the origins of the
full-field ERG b-wave together with other non-linear
effects. Hood et al further investigated the effects of
pharmacological suppression of monkey mfERG
responses to determine the components of mfERG
in human.94 It was found that after administration
of tetradotoxin (TTX) and N-methyl-D-aspartic acid
(NMDA), which blocked most of the inner retinal
contributions from the ganglion cells, the waveform
of monkey mfERG resembled that of human
mfERG. The results suggested that human first-
order mfERG response is dominated by cells of the
outer retina such as the photoreceptors and the on
and off-bipolar cells.
SECOND-ORDER KERNEL COMPONENT
OF MFERG
The waveform of the second-order kernel mfERG
is smaller compared with the first-order kernel and
is therefore more difficult to measure due to poorer
signal-to-noise ratio. It has an initial positive peak
followed by a negative trough and these are labeled
as P1 and N1, respectively (Fig. 3). This second-
order kernel component was proposed to reflect the
inner retinal activity from the retinal ganglion cells.
However, it has been shown that there was poor
correlation between the spatial distributions of
second-order kernel responses and retinal ganglion
cells.325 Therefore, in contrast with the first-order
kernel response, the second-order kernel compo-
nent is not a response generated by specific retinal
cells. It is a measure of how the mfERG response is
APPLICATIONS OF MULTIFOCAL ELECTRORETINOGRAPHY
affected by a preceding flash due to non-linear
adaptive mechanisms of the retina.
ANALYSIS AND DISPLAY OF MFERG RESPONSES
mfERG responses can be analyzed and displayed
in three commonly used options: trace arrays, group
averages, and three-dimensional response density
topography. The trace arrays (Fig. 2, top) are
composed of the individual mfERG responses which
originate from discrete retinal locations and these
basic waveforms should be included in all recording
printouts. The individual mfERG responses can be
selected and grouped for comparisons and com-
monly performed group averaging methods include
ring and quadrant analysis (Fig. 4). Peak implicit
times and response amplitudes are the main
parameters measured during analysis of mfERG.
For the first-order mfERG response, the N1 ampli-
tude is measured from the baseline to the N1 trough
and the P1 amplitude is measured from the N1
trough to the P1 peak. Implicit times are measured
from the onset of the stimulus to the peak of the
waveform. Averaging procedures may be employed
during analysis to eliminate artifacts and to smooth
out the waveforms. However, these procedures may
Fig. 4. Common group averaging methods used in mfERG analysis. Left: Ring averaging of mfERG responses according
to retinal eccentricity from ring 1 (fovea) to ring 6 (peripheral macula). Right: Quadrant averaging of mfERG responses
according to the retinal quadrant, from quadrants 1 to 4.
65
artificially distort the mfERG responses and should
be applied cautiously.324 The three-dimensional
response density topography (Fig. 2, bottom) plots
the response density of the N1 and P1 components
per unit area and provides a graphical overview of
responses at different retinal locations for ease of
visualization.
Factors Affecting mfERG
in Normal Subjects
As with all other investigations, there is a range of
normative values of mfERG parameters due to
individual variation. In normal subjects without
any retinal pathology, several factors can affect the
mfERG responses. Important factors that should be
considered in the analysis of mfERG include age,
severity of cataract, and the refractive error and axial
length status.
INFLUENCE OF AGE ON MFERG
Several studies have investigated the effects of age
on mfERG recordings.5,65,71,73,117,198,208--210,277,298,302
In general, most studies found reductions in mfERG
66 Surv Ophthalmol 52 (1) January--February 2007
response amplitudes and delays in implicit times
with increasing age. Seiple et al found that the
P1 amplitude decreases by appropriately 10.5% per
decade.277 The effects of age on implicit times are
less and were found to increase by about 1% per
decade.277 Tzekov et al also showed that there is
about 5% per decade reduction in P1 response
amplitude, with 1.2% per decade increase in
P1 implicit time associated with aging.302 The
effect of age on mfERG is more marked in the
central retina compared with more peripheral
retina.5,65,71,117,198,277,302 These results highlighted
the importance for each laboratory to develop
an age-matched normative data for mfERG analysis
or for corrections for age be published and
disseminated to mfERG users.
The cause for the age-related changes in mfERG
response is controversial. Fortune and Johnson
suggested that the diminished mfERG response
was mostly accounted by preretinal optical factors
such as higher lens density and smaller pupil size in
older subjects.65 However, Seiple et al showed that
smaller pupil diameters would reduce both the
levels of adaptation and stimulus luminance and
these changes would not result in the age-related
reduction in mfERG amplitude.277 Tam et al also
demonstrated that by removing optical factor due to
the crystalline lens, no significant differences in N1
and P1 amplitudes and P1 implicit time were found
between patients aged 18--25 years and pseudo-
phakic patients aged 70 years or older.298 There was,
however, a significant difference in N1 implicit time
between young phakic and older pseudophakic
subjects, suggesting a neural factor may be re-
sponsible for the mfERG changes in older subjects.
Based on these studies, it is therefore likely that the
age-related mfERG changes are due to both
preretinal optical factors and neural factors such
as loss of photoreceptors and inefficient synaptic
transmission in older patients.71,277,298
INFLUENCE OF CATARACT ON MFERG
As discussed in the last section, preretinal optical
factor such as cataract may influence mfERG
recordings due to light scattering and studies have
therefore evaluated the effects of cataract on
mfERG.228,297,299,315,326 Tam et al studied the effects
of different cataract severity on mfERG record-
ings.299 It was shown that N1 and P1 response
amplitudes from the central macula were signifi-
cantly reduced in subjects with mild or moderate
cataract compared with subjects with very mild
cataract. Tam et al and Palmowski et al also
demonstrated increases in mfERG responses in eyes
which had undergone cataract surgery.228,297 In
LAI ET AL
another study conducted by Wördehoff et al, it was
shown that there were significant increases in P1
response amplitudes in the central macula after
cataract surgery, while no significant changes in N1
and P1 implicit times were observed.315
Besides assessing the mfERG changes in cataract
patients, studies using artificial light scattering have
also been performed to mimic the effects of cataract
on mfERG.8,31,296 Similar to the findings in cataract
patients, experimental light scattering resulted
in reduction in mfERG responses particularly in
the central retina.8,31,296 Chan et al showed that
the peripheral mfERG response amplitude densities
may also increase due to light scattering.31 Because
lens opacifications are relatively common in
older subjects, it is important that the severity of
cataract be considered during analysis of mfERG
recordings.
INFLUENCE OF REFRACTIVE ERROR AND AXIAL
LENGTH ON MFERG
Changes in refractive error and axial length in
normal subjects may also affect the mfERG
recordings. Kawabata and Adachi-Usami studied
the effects of refractive error on mfERG in normal
young subjects.125 In order to minimize the
differences in retinal image caused by the correc-
tive lens, the test distance was adjusted according
to the subject’s refractive error. It was shown that
amplitudes were reduced and implicit times were
delayed as refractive errors increased. Chan and
Mohidin also showed that increase in axial length
is associated with reductions in both the first- and
second-order kernel response amplitudes.30 Be-
cause high myopia is associated with longer axial
length, the mfERG changes in myopia may be
related to the morphological changes associated
with increased axial length. One of the postulated
causes of the reduced mfERG response is the loss
of cone function associated with myopia and
longer axial length much as the full-field ERG
may be reduced in these patients.125 In another
study by Chen et al, myopic patients were found
to have significantly longer P1 implicit time
compared with emmetropes.41 Analysis showed
that refractive error contributed to a greater
proportion of variance in the implicit time
changes compared with axial length.41 This
suggested that the mfERG alterations in myopia
might not be due to anatomical changes alone.
Based on these studies, the subject’s refractive
error and axial length status should therefore be
accounted for when analyzing mfERG.
APPLICATIONS OF MULTIFOCAL ELECTRORETINOGRAPHY
Clinical Applications of mfERG
in Acquired Retinal Diseases
AGE-RELATED MACULAR DEGENERATION
Age-related macular degeneration (AMD) is
a common cause of visual impairment in the older
population and mfERG has been used to evaluate
the extent of retinal dysfunction in AMD pa-
tients.14,54,56,57,72,91,110,122,151,152,167,172,228,248,258 Pa-
tients with early AMD were found to have
significant reduction in the foveal P1 amplitude
and delay in N1 implicit time compared with normal
age-matched controls.167 The extent of mfERG
changes is influenced by the severity of AMD as
patients with neovascular AMD had more severe
reductions in mfERG response amplitudes and
delays in implicit times compared with patients with
dry AMD.110,152 Palmowski et al reported that the
functional changes demonstrated by mfERG corre-
sponded well with the anatomical changes detected
on fluorescein angiography.228 However, this was
only based on the results from three AMD patients
and subsequent studies have demonstrated that the
mfERG abnormality tends to be more diffuse
compared with the morphological changes.72,91
Gerth et al evaluated all the first-order mfERG
responses individually in AMD patients and com-
pared them with the changes on fundus photogra-
phy and fluorescein angiography.72 Only 23% of
eyes showed significant correlation between various
mfERG abnormalities and morphological changes.
Implicit times were found to be more sensitive in
detecting abnormal retinal responses compared
with response density.
Although mfERG appears to be useful in doc-
umenting functional changes in AMD patients, it
was unclear how it compares with subjective
measures of visual function. Feigl et al compared
the use of mfERG and various subjective visual
function measures such as color vision and contrast
sensitivity in assessing patients with early AMD.57 It
was found that mfERG failed to discriminate
between control and early AMD subjects, whereas
it was possible to use subjective measures to
discriminate the two groups. By using a special
protocol for recording rod-mediated mfERG instead
of the conventional cone-mediated mfERG, Feigl
et al also showed that rod-mediated mfERG may be
more sensitive in detecting retinal dysfunction in
early AMD compared with light-adapted cone-
mediated mfERG.55,56 These results suggest the
rod system might be affected earlier than the light-
adapted cone system in early AMD. Feigl et al
further demonstrated that the use of a global-flash
mfERG stimulus by inserting a global bright flash
between two dark frames may also detect deficits in
67
early AMD before the conventional mfERG stimu-
lus.54 Further studies to optimize the mfERG
parameters for the assessment of retinal function
in AMD should be conducted.
DIABETIC RETINOPATHY
Diabetic retinopathy is a major complication of
diabetes mellitus and may lead to significant visual
impairment. mfERG has been used in a number of
studies to evaluate the retinal function in diabetic
patients and most studies have demonstrated that
implicit time measures are more sensitive compared
with amplitude changes in detecting retinal dys-
function.66,79,81,82,230,301,327 Palmowski et al assessed
the retinal function in diabetic patients with or
without diabetic retinopathy by analyzing both the
first- and second-order mfERG responses.230 Pa-
tients with diabetic retinopathy had significantly
lower response amplitudes and longer implicit times
for both the first- and second-order components
compared with control. In diabetic patients without
retinopathy, only the amplitude of the second-order
component was reduced. Because the second-order
component reflects the dynamics of adaptive mech-
anisms that are mainly influenced by the inner
retinal activity from the retinal ganglion cells, the
findings suggested that diabetic patients may de-
velop inner retinal impairment prior to outer retinal
dysfunction. Tyrberg et al demonstrated that di-
abetic patients with retinopathy had significantly
longer second-order mfERG implicit times com-
pared with patients without any retinopathy.301
Fortune et al performed mfERG in diabetic patients
with or without diabetic retinopathy to evaluate the
local retinal abnormalities.66 Results showed that
mfERG implicit times from locations with clinically
visible retinopathy were markedly delayed compared
with normal control. Implicit times of responses
from areas adjacent to locations with visible reti-
nopathy were also delayed and mfERG is therefore
sensitive in detecting local retinal dysfunction
before retinopathy develops. In another study,
Mita-Harris found that the first- and second-order
response amplitudes were significantly higher in
diabetic patients without retinopathy compared with
control.197 Klemp et al also showed that transient
hyperglycemic state in diabetic patients without
retinopathy was associated with shortenings of
implicit times for the P1 and N2 components of
the first-order kernel response and all components
of the second-order kernel response.133,134 During
acute normoglycemia, diabetic patients without
retinopathy were found to have prolonged mfERG
implicit times compared with healthy controls and
the delay was proportional to the patients’ level of
68 Surv Ophthalmol 52 (1) January--February 2007
chronic hyperglycemia.134 These results support the
hypothesis that hyperglycemia may accelerate reti-
nal metabolism with increase in retinal blood flow in
early diabetes. The application of mfERG has thus
enhanced the understanding of early retinal func-
tional changes in diabetes.
Several studies have also used mfERG to evaluate
the retinal function in diabetic patients with
clinically significant macular edema
(CSME).79,107,178,179,319 Foveal thickness as mea-
sured on optical coherence tomography (OCT)
was found to be significantly correlated with mfERG
amplitudes and implicit times.178,319 Retinal loca-
tions with CSME had significant delays in mfERG
implicit times with reduction in response ampli-
tude.79 The changes in implicit times were found to
be more diffuse compared with amplitude changes
and extended to areas without clinically manifesting
macular edema.
Besides analyzing the first- and second-order
mfERG responses, analysis of multifocal oscillatory
potentials (OP) has also been shown to be useful in
the assessment of retinal dysfunction in diabetic
patients.12,79,157,219 Onozu and Yamamoto recorded
multifocal OP using a bandpass filter of 100--300 Hz
and demonstrated that patients with diabetic reti-
nopathy had reduced multifocal OP amplitude and
delayed implicit times.219 Another technique more
commonly used to evaluate multifocal OP is with the
use of a slow flash mfERG (sf-mfERG) by inserting
three dark frames in between the multifocal
stimuli.317 Because higher order effects are fre-
quently superimposed on the waveform of standard
first-order mfERG response, this may cause difficulty
in the measurement and interpretation of the later
mfERG components.11 The insertion of dark frames
to increase the multifocal flashes interval enabled
retinal responses to develop and decay more
completely and allowed clearer assessment of first-
order kernel responses including OP. Using the sf-
mfERG, Bearse et al demonstrated retinal functional
abnormalities can occur in diabetic patients without
retinopathy.11 Greenstein et al also showed that
there was an absence of macular OP in diabetic
patients with CSME.79 In another study by Kurten-
bach et al, it was shown that there were delays in
both the first- and second-order multifocal OP
implicit times in diabetic patients without retinop-
athy, suggesting the presence of early retinal
dysfunction in diabetic patients.157 Bearse et al also
investigated the local multifocal OP in diabetic
patients.12 In order to increase the signal-to-noise
ratio, the first- and second-order sf-mfERG kernels
were combined to form a summed second-order
kernel OP by digital filtering before isolation of
multifocal OP.12 It was demonstrated that both the
LAI ET AL
summed second-order kernel OP and the first-order
kernel OP were frequently abnormal in diabetic
eyes. However, some differences exist between the
first- and second-order OP as the summed second-
order kernel OP were significantly associated with
the local retinal sites of clinical retinopathy, whereas
the first-order kernel OP were not. These findings
suggest that the effects of fast adaptive mechanisms
are more likely to be impaired in locations with
diabetic retinopathy.
As the early effects of diabetic retinopathy appear
to cause more changes in second-order response
compared with first-order response due to alter-
ations in the fast adaptive mechanisms, Shimada et
al used a special stimulus to evaluate the fast
adaptive effects caused by interactions of flashes in
diabetic patients.281 A periodic global flash is
inserted in between the multifocal stimuli and this
flash will only contribute to the focal response if it
was preceded by a multifocal stimulus.279 This
stimulus results in a direct response due to focal
flash and an induced response due to interaction of
focal and global flash and was proposed to enhance
responses from the ganglion cell and the optic
nerve head component (ONHC).63,222,282 It was
shown that diabetic patients without retinopathy
had significantly lower amplitude in the induced
component, whereas the direct response was similar
compared with controls without diabetes.281 The
application of this multifocal stimulus with periodic
global flash may enable early detection of retinal
dysfunction in diabetic patients.
The technical and analysis settings of mfERG
should be considered when using implicit times to
assess retinal function in diabetic retinopathy.
Schneck et al compared two different methods for
measuring the first-order mfERG implicit times
known as template stretching and template slid-
ing.268 The template stretching method scales the
entire waveform by multiplying a scaling factor for
best fit to a template based on normal data. This will
therefore cause more prolongation in implicit times
for the later portions of the mfERG response. For
the template sliding technique, the difference
between the waveform and template is added by
a fixed amount. Diabetic patients were found to
have more implicit time abnormalities with the
template stretching method compared with tem-
plate sliding. This is because template-stretching
method caused less variability in implicit time
measures and should therefore be used in assessing
diabetic retinopathy. Han et al also proposed using
the amplification filter cutoffs of 10--100 Hz instead
of 10--300 Hz to improve the signal-to-noise ratio
and to lower the inter-subject variability.82 It was
shown that recordings using the lower high
APPLICATIONS OF MULTIFOCAL ELECTRORETINOGRAPHY
frequency cut-off of 100Hz enabled identification of
more implicit time abnormalities in diabetic pa-
tients without retinopathy.
Apart from using mfERG to evaluate and monitor
retinal function in diabetic patients, longitudinal
studies have also studied the use of mfERG in
predicting future development of diabetic retinop-
athy. Han et al assessed the local first-order mfERG
implicit times in patients with nonproliferative
diabetic retinopathy to determine the association
with areas of new retinopathy 1 year later.83 It was
shown that 70% of areas with new retinopathy had
delayed implicit time at baseline, whereas only 24%
of regions without new retinopathy had abnormal
baseline implicit time. Amplitude changes were not
found to be useful in predicting subsequent diabetic
retinopathy. It was concluded that localized retinal
dysfunction as reflected by mfERG implicit time
delays often precedes the onset of new signs of
diabetic retinopathy. Han et al further improved the
prediction of diabetic retinopathy by developing
a model which included mfERG implicit times and
risk factors of diabetic retinopathy.84 By using
mfERG implicit time, duration of diabetes, presence
or absence of diabetic retinopathy at baseline, and
blood glucose level at the initial visit, this model had
an expected sensitivity of 86% and specificity of 84%
in predicting sites of future diabetic retinopathy in
12 months.
CENTRAL SEROUS CHORIORETINOPATHY
Central serous chorioretinopathy (CSC) is a dis-
ease characterized by the spontaneous development
of serous retinal detachment at the macula. mfERG
has been shown to be useful in assessing the retinal
functional impairments in patients with
CSC.35,48,111,149,151,172,187,229,232,292--294,305,329 During
acute CSC, retinal dysfunction is reflected by
reduction in mfERG response amplitudes and delay
in implicit times.35,111,187,305 Marmor and Tan
demonstrated that mfERG response amplitudes
were not only depressed in areas of serous retinal
detachment but also extended beyond the area of
detachment.187 This suggests a more widespread
area of retinal dysfunction occurs as compared with
the localized subretinal fluid seen clinically. With
the use of mfERG, it has also been demonstrated
that the fellow eye of patients with CSC may have
abnormal mfERG responses.35,48,187 These findings
suggest that CSC is a bilateral disorder and may be
caused by a diffuse pathologic process affecting the
choroid and/or the retinal pigment epithelium
(RPE). However, this remains controversial since
another study by Vajaranant et al failed to demon-
strate significant changes in mfERG responses in the
69
clinically normal fellow eye of patients with CSC.305
This might be due to a larger range of normal value
in the control group or as a result of variation of the
disease process so that not all patients with CSC will
have bilateral involvement. Further research to
clarify these findings will be useful.
Another application of mfERG in CSC is in the
monitoring of the clinical course of the disease
(Fig. 5). It has been shown that mfERG abnormal-
ities may persist even after resolution of the
subretinal fluid clinically.35,48,292--294 mfERG may
therefore have a useful role in providing an
objective measure of retinal function in research
on the treatment for CSC.
MACULAR HOLE
mfERG has been used for the objective assess-
ment of macular function in patients with macular
hole.7,106,201,216,251,283,295 Patients with macular hole
were found to have marked reductions in mfERG
response densities in both the foveal and perifoveal
regions.283,295 After successful macular hole surgery,
improvement in foveal and perifoveal mfERG re-
sponse densities could be observed.201,283 Apostolo-
poulos et al assessed the correlation between OCT
and mfERG findings in patients who had macular
hole surgery.7 It was found that although visual
acuity significantly correlated with the foveal thick-
ness measured by OCT, mfERG response densities
did not correlate with visual acuity and foveal
thickness. The mfERG findings suggested that
retinal function remained impaired despite success-
ful macular hole surgery.
mfERG has also been applied to investigate the
potential adverse effects associated with macular
hole surgery.106,216 Oh et al found that none of the
patients with visual field defects after macular hole
surgery had specific abnormalities on mfERG and
the findings suggested arteriolar occlusion is not
a likely cause for the visual field defects.216 Horio et
al also used mfERG to evaluate the functional
outcome in patients who underwent internal limit-
ing membrane (ILM) peeling in macular hole
surgery with or without indocyanine green (ICG)
dye staining.106 It was shown that there were no
significant differences in P1 implicit time and
amplitude ratios between the two groups. Weinberg-
er et al also demonstrated that there was regular
pattern of mfERG amplitudes after macular hole
surgery with ICG-assisted ILM peeling.311 The
results suggested the cause of potential ICG-related
retinal toxicity may be due to its effect on retinal
ganglion cells rather than the outer retina. However,
the lack of mfERG changes in these studies may also
be due to insufficient sensitivity of the mfERG
70 Surv Ophthalmol 52 (1) January--February 2007 LAI ET AL

Fig. 5. Serial mfERG changes in a patient with acute central serous chorioretinopathy. Top Left: OCT demonstrating
a pocket of subretinal fluid beneath the fovea. Bottom Left: mfERG trace array and three-dimensional topography plot
demonstrating the diminished response at the central macula corresponding with the location of the subretinal fluid. Top
Right: OCT of the patient three months after presentation with complete resolution of the subretinal fluid. Bottom Right:
mfERG trace array and three-dimensional topography showing recovery of the central retinal response.

parameters in detecting such toxicity. Further
studies may consider the use of other mfERG
measurements such as second-order kernel re-
sponses and multifocal OP in evaluating the
potential retinal damage associated with macular
hole surgery.
EPIRETINAL MEMBRANE
Idiopathic epiretinal membranes (ERM) or mac-
ular puckers may cause visual impairment with
patients developing decreased vision or metamor-
phopsia. mfERG has been applied in the assessment
of macular function in patients with ERM.10,166,200
(Fig. 6). Moschos et al performed mfERG in
patients who underwent successful ERM surgery.200
Preoperatively, there was reduction in the response
densities in both the foveal and parafoveal regions,
suggesting substantial functional alteration of the
retina underlying the ERM. Postoperatively, signifi-
cant increases in mfERG response densities were
observed over time and the improvement continued
6 months after the operation. The authors sug-
gested the improvement in mfERG responses may
be due to resolution of the macular edema
associated with the ERM. However, OCT was not
performed in this study and it was uncertain
whether mfERG findings correlated with macular
thickness. In another study carried out by Li et al,
both OCT and mfERG were performed in patients
with ERM.166 It was found that mfERG response
amplitude was significantly lower with delay in
implicit times in ERM patients. Although foveal
thickness measured on OCT negatively correlated
with visual acuity, no significant correlation was
found between mfERG amplitude and both visual
acuity and foveal thickness. Balayre et al also used
mfERG to evaluate the retinal functional changes
after ERM surgery with trypan blue staining and
results demonstrated that trypan blue did not result
in any obvious retinal toxicity.10 The mfERG findings
provided an objective measurement of the perioper-
ative retinal function, and assisted in the under-
standing of the retinal pathophysiology in ERM.
APPLICATIONS OF MULTIFOCAL ELECTRORETINOGRAPHY 71

Fig. 6. Preoperative and postoperative mfERG in a patient with epiretinal membrane (ERM). Left: Fundus photograph,
trace array and three-dimensional mfERG topography before ERM surgery. The visual acuity was 20/70 and mfERG
demonstrated foveal and parafoveal reductions in retinal response amplitudes. Right: Fundus photograph, trace array,
and three-dimensional mfERG topography of the patient 3 months after ERM surgery. The visual acuity improved to 20/30
and the mfERG responses improved after surgical removal of the ERM.

RETINAL VASCULAR OCCLUSIONS
Branch retinal artery occlusion (BRAO) causes
localized visual field defect due to damage to the
inner two-thirds of the retina, involving the inner
nuclear layer, inner plexiform layer, ganglion cells
and the nerve fiber layers. mfERG has been used to
document localized retinal dysfunction in patients
with BRAO.88,218,313,318 The areas of mfERG abnor-
malities generally correlated well with the localized
defects detected on perimetry.88,313 Studies have
also been performed in BRAO patients to un-
derstand the influence of inner retinal damage on
the first- and second-order mfERG responses.88,218
Hasegawa et al demonstrated that there were
significant reductions in both the first- and sec-
ond-order response amplitudes in the affected area
compared with the unaffected area.88 The reduc-
tion was more marked for the second-order re-
sponse and mapping of the second-order response
correlated better with the perimetry findings
compared with the first-order response. This dem-
onstrated that the second-order mfERG component
may be a sensitive indicator for assessing inner
retinal dysfunction caused by impairment of cells in
the inner plexiform layer or retinal ganglion cells as
observed in BRAO.
mfERG has also been used to assess the regional
variation in recovery of retinal function after
BRAO.116 Doppler flow meter was used to assess
the retinal microcirculation and results were com-
pared with mfERG findings in the juxtapapillary and
paramacular areas. It was found that while there
were similar reductions in the mfERG amplitude
and doppler flow ratios of the affected eye to the
fellow eye in the juxtapapillary area, the mfERG
amplitude ratio was lower in the paramacular area
compared with the doppler flow ratio. This suggests
recovery of retinal function after BRAO occurred
faster in the juxtapapillary area compared with the
paramacular area.
72 Surv Ophthalmol 52 (1) January--February 2007
Similar to BRAO, branch retinal vein occlusion
(BRVO) can cause visual field defect due to localized
disturbance in retinal perfusion. mfERG has been
applied to evaluate the extent of retinal dysfunction
in patients with BRVO and was found to correlate
with the visual field findings.113,313 Thrombotic areas
of the retina were also found to have significantly
lower response amplitudes and longer mfERG
implicit times compared with non-thrombotic
areas.113 The main mfERG abnormality at the central
macula is the reduction of response amplitude,
whereas delay in implicit time was the main abnor-
mality in the quadrant affected by BRVO.114 The
foveal retinal thickness measured on OCT and visual
acuity was also found to have a significant negative
correlation with the P1 response amplitude.115
The retinal function after central retinal vein
occlusion (CRVO) has also been evaluated using
mfERG.50,149 Kretschmann et al performed mfERG
in patients with CRVO and reduced P1 amplitudes
and delayed P1 implicit times were observed in both
the affected and fellow eyes compared with normal
controls.149 Using wide-field mfERG (WF-mfERG),
which allowed recording of mfERG responses from
up to the central 90 of the retina, Dolan et al
showed that mfERG abnormalities are common in
both the affected and fellow eyes of CRVO
patients.50 Delays in P1 implicit times at the central
and peripheral retina were found in 98% and 91%
of eyes with CRVO, respectively. The mfERG
changes observed in the fellow eyes were probably
due to abnormal retinal function associated with
systemic risk factors of CRVO such as hypertension,
diabetes, and hypercholesterolemia. Significant cor-
relations between central P1 mfERG amplitude and
both 30 Hz photopic flicker amplitude and latency
responses were also observed. Because the flicker
amplitude has been shown to be a good predictor
for neovascular complication in CRVO, further
study will be useful in assessing the role of WF-
mfERG measurements as prognostic indicators in
patients with CRVO.
TOXICITY DUE TO SYSTEMIC AGENTS
Chloroquine and Hydroxychloroquine
Antimalarial drugs, such as chloroquine and
hydroxychloroquine, are commonly used in the
treatment of rheumatologic diseases, such as sys-
temic lupus erythematosus and rheumatoid arthri-
tis. Irreversible retinal toxicity may be associated
with long-term use of the drugs, causing the
development of bull’s eye maculopathy in the late
stage. mfERG has been used in the assessment of
chloroquine and hydroxychloroquine retinal toxic-
ity.130,162,190,192,204,234,285,303 The most characteristic
LAI ET AL
mfERG findings specific to chloroquine and hydrox-
ychloroquine retinal toxicity is the parafoveal re-
duction in P1 response amplitude and delays in N1
and P1 implicit times130,192,303 (Fig. 7). Using
mfERG, it has been shown that patients on long-
term hydroxychloroquine therapy may have retinal
functional abnormalities despite having normal
visual acuity and absence of fundus abnormali-
ties.192,204,234,285 So et al demonstrated the presence
of pericentral depression in mfERG response
amplitudes in three (50%) of the six patients who
had been on hydroxychloroquine for more than 5
years.285 Moschos et al also showed that eight (40%)
of the 20 patients who had been on hydroxychlor-
oquine treatment for less than 5 years had mfERG
abnormalities.204 Hydroxychloroquine use was dis-
continued in patients who had severe reduction in
mfERG responses and the mfERG abnormality
returned to normal in some patients. This suggests
that retinal dysfunction caused by hydroxychloro-
quine is potentially reversible. In another study by
Maturi et al, mfERG abnormalities were found in 11
(58%) of the 19 patients who were on long-term
hydroxychloroquine therapy.192 All patients except
one had normal Amsler grid testing and color
vision. The authors identified four patterns of
mfERG amplitude abnormalities including para-
central loss, foveal loss, peripheral loss, and gener-
alized loss. The evolution of hydroxychloroquine
retinopathy was demonstrated in one patient and
there was gradual prolongation of P1 implicit time
during follow-up. Lai et al reported the longitudinal
mfERG changes in patients on hydroxychloro-
quine.162 After a mean follow-up of 17 months, it
was shown that there was slight but statistically
significant increase in P1 implicit time in patients
who continued taking hydroxychloroquine. Results
also showed a significant moderate negative corre-
lation between the total cumulative dose of hydrox-
ychloroquine used and both the N1 and P1 response
amplitudes, suggesting that the total dose of
hydroxychloroquine might play an important role
in influencing the mfERG abnormalities. Results
from these studies demonstrated that retinal dys-
function is common in patients on long-term
hydroxychloroquine therapy. The use of mfERG
for evaluating hydroxychloroquine retinopathy ap-
peared to detect retinal physiological changes
earlier than other testing modalities and may enable
documentation of preclinical stage of hydroxychlor-
oquine retinopathy.192
Although it was commonly believed that the sites
of hydroxychloroquine toxicity is at the RPE and
photoreceptor levels, the exact mechanism of
hydroxychloroquine toxicity remained uncertain.
It has also been suggested that hydroxychloroquine
APPLICATIONS OF MULTIFOCAL ELECTRORETINOGRAPHY 73

Fig. 7. mfERG findings in a patient with chloroquine retinopathy. Top: Fundus photograph of the characteristic bull’s
eye maculopathy in the left eye of a patient with visual acuity of 20/30 who has been on chloroquine therapy for 10 years.
Bottom: Trace array and three-dimensional topography demonstrating the parafoveal loss in mfERG responses
characteristic of toxic maculopathy caused by chloroquine or hydroxychloroquine.

may be toxic to the retinal ganglion cells. In order to
investigate the effects of hydroxychloroquine to
inner retinal function, Penrose et al used a special
mfERG stimulus to measure the second-order re-
sponse which evaluated the adaptation effects of the
retina in patients taking hydroxychloroquine.234 It
was found that this protocol allowed earlier de-
tection of focal abnormalities in hydroxychloro-
quine retinopathy. However, some patients still had
abnormal first-order mfERG responses to the classic
mfERG stimulus despite having normal second-
order response to the new stimulus. Therefore the
use of this stimulus in assessing hydroxychloroquine
retinopathy requires further evaluation.
Vigabatrin
Vigabatrin is an irreversible inhibitor of gamma-
aminobutyric acid (GABA) transaminase and is used
in the treatment of epilepsy. One of the side effects
associated with vigabatrin is persistent visual field
constriction. Electrophysiological studies have sug-
gested this might be due to the toxic effects of
vigabatrin on the retina. Because the visual field
74 Surv Ophthalmol 52 (1) January--February 2007
constrictions are often localized binasally, mfERG
has been used to evaluate the retinal dysfunction
topographically in patients taking vigaba-
trin.18,86,120,165,182,239,255 Using mfERG, it was dem-
onstrated that patients with visual field defects
attributed to vigabatrin had reduced generalized
or peripheral mfERG response ampli-
tudes.18,86,120,165,182,239,255 The abnormalities in
mfERG response amplitudes appeared to correlate
well with the visual field defects in some cases.86,239
However, the abnormalities may also be more
diffuse compared with the visual field findings.86,165
Besch et al further investigated the multifocal OP
and second-order mfERG responses in patients on
vigabatrin who had visual field defects.18 It was
found that these patients had delayed multifocal OP
and in cases with severe visual field defects, there
were also delays in second-order mfERG implicit
times. These findings suggested that vigabatrin-
related visual field defects may be a result of inner
retinal dysfunction of the retinal ganglion cells.
A limitation of conventional mfERG in the
assessment of retinal function is the restriction of
recordings of responses from the central 50--60 of
the retina, and therefore it is unable to detect more
peripheral retinal dysfunction caused by vigabatrin.
The WF-mfERG was developed as a technique to
objectively measure more peripheral retinal func-
tion and has been applied in the evaluation of visual
field constrictions in vigabatrin patients.193,194
McDonagh et al conducted a study to evaluate the
use of WF-mfERG in patients taking vigabatrin.194
Among all the WF-mfERG parameters, the most
consistent overall predictor of bilateral visual field
defects was the difference between the central and
peripheral implicit times. Using this parameter, it
was shown that WF-mfERG had 100% sensitivity and
86% specificity in detecting patients with visual field
defect. This study demonstrated that WF-mfERG can
objectively detect peripheral retinal dysfunction in
patients taking vigabatrin and larger study is un-
dergoing to validate these results.
Others
Amiodarone
Amiodarone is used in the treatment of cardiac
arrhythmia and congestive heart failure. Long-term
use of amiodarone has been associated with full-
field and pattern ERG abnormalities. Shaikh et al
performed mfERG in patients who had been on
long-term amiodarone therapy to evaluate the
potential retinal toxicity topographically.278 It was
shown that some patients had subnormal P1
amplitudes and mild prolongation in P1 implicit
times. The authors believed that the mfERG
LAI ET AL
changes were probably age-related or due to testing
variability and further studies should be performed
to determine the extent of retinal toxicity associated
with long-term amiodarone therapy.
Sildenafil
Sildenafil is a drug used in the treatment of
erectile dysfunction and one of the reported side
effects is color vision disturbance. mfERG has been
used to evaluate the acute effects of sildenafil on
central retinal function.177 Luu et al performed
mfERG recordings in 14 healthy subjects given
sildenafil.177 At 1 hour after the intake of sildenafil,
there were slight but significant reductions in P1
amplitudes and delays in P1 implicit times at all
retinal eccentricities. The mfERG changes were
largest in the central macula with around 20%
reduction in P1 amplitude and 5--9% increase in P1
implicit times. The mfERG changes persisted for up
to five hours after taking sildenafil in some patients.
The mfERG findings provided objective evidence
that sildenafil may have an acute effect in macular
function which may account for the transient visual
disturbances observed by the patients.
Deferoxamine
Deferoxamine is a chelating agent used for iron
overload in patients requiring long-term blood
transfusion and its use may be associated with toxic
retinopathy. Schmidt et al documented reduction in
mfERG amplitude in the central retina in a patient
who developed bull’s eye maculopathy after deferox-
amine therapy.267 Kertes et al showed that there
were bilateral reductions in response densities at the
central retina which corresponded with the pigmen-
tary changes observed in deferoxamine toxicity.132
After termination of the drug, the decline in retinal
function stabilized as reflected by mfERG. Serial
mfERG recordings allowed objective quantification
and monitoring of retinal toxicity caused by
deferoxamine.
Ethambutol
Ethambutol is used in the treatment of tubercu-
losis and its use may cause toxic optic neuropathy.
Studies have also demonstrated that ethambutol
may be toxic at the retinal level and macular toxicity
associated with ethambutol-related optic neuropa-
thy has been documented using mfERG.163 Lai et al
reported generalised reduction in central mfERG
responses in a patient with ethambutol-induced
optic neuropathy.163 The area of mfERG abnormal-
ity was more extensive than the central scotoma
detected on automated perimetry, indicating diffuse
impairment in macular function. After cessation of
APPLICATIONS OF MULTIFOCAL ELECTRORETINOGRAPHY
ethambutol, increase in mfERG response paralleled
with the improvement in visual acuity. Behbehani et
al also reported mfERG response abnormalities in
four patients with ethambutol associated visual
loss.15 Two of the patients had no visible optic nerve
or fundus abnormalities. Analysis showed that
patients had significant reduction in N1 response
amplitude compared with controls. Based on these
studies, mfERG may be a useful tool in the diagnosis
and serial assessment of ethambutol-related retinal
toxicity. Some of the findings however might also be
related to eccentric fixation caused by ethambutol-
induced optic neuropathy and therefore causing
reduction in retinal response amplitude.
Mercury
Mercury is a potent neurotoxin that may cause
retinal toxicity and mfERG has been used to
evaluate the toxic effects of mercury to the central
retina.307 Ventura et al performed mfERG in
workers of fluorescent-lamp manufacturing plants
who had chronic exposure to mercury vapor.307 It
was found that the workers had significant re-
ductions in N1 and P1 amplitudes at all retinal
eccentricities and delay in P1 implicit time at the
fovea compared with control. The mfERG findings
provide objective evidence that chronic mercury
exposure may result in retinal toxicity, causing outer
segment and bipolar cell damage.
Nefazodone
Nefazodone is an anti-depressant which blocks
postsynaptic serotonin type-2 (5HT2) receptors and
its use has been associated with blurred vision and
visual disturbances. Luu et al reported the use of
mfERG in evaluating retinal dysfunction in a patient
with severe bilateral visual loss three years after
nefazodone therapy for eight weeks.174 No abnor-
mality was detected using conventional full-field
ERG. The use of mfERG demonstrated severe
depression in mfERG responses over the central
retina with sparing of the nasal retinal responses,
suggesting that nefazodone may cause central
retinal toxicity.
Thallium
Thallium poisoning may cause visual impairment
due to optic atrophy. mfERG has been applied to
assess the retinal toxicity in a patient with chronic
thallium poisoning in which the full-field ERG was
normal.266 Thallium poisoning led to reduction in
central mfERG response amplitude with preserva-
tion of the responses from the mid-peripheral
retina. The result suggested in addition to optic
neuropathy, thallium poisoning may also result in
75
retinal toxicity at the central retina. However,
eccentric fixation caused by the optic neuropathy
might also have accounted some of the mfERG
abnormalities.
Miscellaneous
Drugs such as methotrexate and rifabutin have
been implicated to cause retinal toxicity and
patients were found to have abnormal full-field
ERG in which the responses improved on termina-
tion of the drugs.240,241 mfERG recordings were
carried out in these patients and the normal mfERG
suggested that central retinal function was not
affected in these patients. However, in the patient
with methotrexate retinal toxicity, mfERG was
performed only after the drug was stopped and
therefore it was uncertain whether impairment in
macular function occurred when the patient was still
on treatment.241 mfERG has also demonstrated that
patients receiving antiviral therapy with alpha-2a
interferon and ribavirin for chronic hepatitis C
might develop subclinical retinal toxicity as shown
by delayed central P1 response implicit times.45
TRAUMA
Phototoxic Retinopathy: Solar and Welding
Arc Exposure
Prolonged exposure to bright light, such as the
sun and welding arc, may result in phototoxic
retinopathy and mfERG has been used to assess
the functional damage in phototoxic retinopa-
thy.46,149,181,183,264 Denk et al showed that there
was persistent mfERG abnormality in a patient 9
months after phototoxic maculopathy caused by
welding arc.46 Mack et al also demonstrated the use
of mfERG in detecting foveal dysfunction in four
patients who had solar phototoxic retinopathy.181 In
another study by Schatz et al, mfERG together with
OCT were used in the monitoring of solar retinop-
athy.264 In both patients, the initial reductions in
response amplitudes normalized at subsequent
follow-up. These cases illustrated that mfERG can
be useful in the assessment of phototoxic retinop-
athy especially in cases with absent or minimal
fundus changes.
Commotio Retinae and Traumatic Macular
Hole after Blunt Trauma
Commotio retinae and traumatic macular hole
may occur after blunt trauma and mfERG has been
used to evaluate the central retinal damage follow-
ing blunt trauma.151,164,242 Purvin and Maturi
performed mfERG in a patient who developed
bilateral central scotoma after motor racing
76 Surv Ophthalmol 52 (1) January--February 2007
accident.242 Clinical examination showed no evi-
dence of pathology involving the optic disks and
macula. However, the use of mfERG demonstrated
marked reduction in central retinal response
amplitude that corresponded to the scotoma ob-
served. The use of mfERG in the absence of fundus
abnormality confirmed a diagnosis of commotio
retinae. Lai et al also studied the clinical course in
a patient who developed commotion retinae and
traumatic macular hole after being hit by a soccer
ball.164 At the initial presentation, mfERG showed
a well-demarcated depression in retinal response
corresponding to the visual field defect caused by
the commotio retinae as well as depressed foveal
response due to the traumatic macular hole (Fig. 8).
The macular hole closed spontaneously after 4
months. The patient developed improvement in
visual acuity but the paracentral scotoma persisted.
Follow-up mfERG showed recovery of the foveal
response as a result of spontaneous closure of the
traumatic macular hole. However the well-demar-
cated area of reduced retinal response density
persisted and the findings supported that perma-
nent visual loss following commotio retinae may
occur due to irreversible damage to the photore-
ceptors.
OTHER ACQUIRED RETINOPATHY
Multiple Evanescent White Dot Syndrome
(MEWDS) and Multifocal Choroiditis (MFC)
Multiple evanescent white dot syndrome
(MEWDS) is an acute unilateral multifocal retinitis
characterized by numerous discrete white dots
around the paramacular area at the RPE level.
Patients usually complain of photopsia, scotoma
with decreased vision, and visual field examination
may reveal enlargement of the blind spot. mfERG
has been used to evaluate the retinal function in
patients with MEWDS and has demonstrated local-
ized area of retinal dysfunction corresponding to
the scotoma which extends from the blind spot
(Fig. 9).23,40,58,108,217 Furthermore, mfERG also
showed more widespread retinal dysfunction com-
pared with subjective visual field testing. The natural
course of mfERG abnormalities in MEWDS have
also been studied longitudinally and recovery of
mfERG responses to normal level paralleled with
resolution of symptoms and clinical findings.40,58,217
Feigl et al showed that MEWDS patients who
presented within seven days of symptoms had
supernormal N1 and P1 mfERG amplitudes with
normal implicit times.58 This was followed by
decrease in response amplitudes two weeks after
onset of symptoms. The mfERG findings may reflect
early photoreceptor disturbances associated with
LAI ET AL
MEWDS. The application of mfERG can assist in the
evaluation of early stages of MEWDS as the retinal
findings may be subtle and easily overlooked at the
early stage.
mfERG has also been used to differentiate
MEWDS with other ocular inflammatory conditions
like multifocal choroiditis (MFC). Oh et al reported
the use of mfERG in 14 eyes with MFC and 7 eyes
with MEWDS.217 mfERG demonstrated focal area of
reduced retinal function corresponding to the blind
spot enlargement in all patients with MEWDS,
whereas only 50% of patients with MFC had focal
loss in mfERG responses corresponding to the
scotoma. MEWDS patients also had less global
mfERG dysfunction compared with MFC patients.
During follow-up, all MEWDS patients had nearly
complete recovery of retinal function on mfERG
whereas none of the patients with MFC had full
recovery in mfERG responses. This finding in-
dicated that MEWDS causes little permanent dam-
age in retinal function whereas MFC may result in
permanent retinal dysfunction. Watzke and Shults
also reported that subnormal first- and second-order
mfERG abnormalities persisted throughout the
posterior pole in patients who recovered from
MEWDS and MFC.310 The abnormalities in sec-
ond-order response were more severe compared
with first-order response and this suggested that the
inner retinal adaptive mechanisms are also affected
in these patients.
Acute Zonal Occult Outer Retinopathy (AZOOR)
Acute zonal occult outer retinopathy (AZOOR) is
a disease characterized by severe visual field loss and
abnormal full-field ERG in the presence of normal
fundus appearance and fluorescein angiography.
mfERG has been used to evaluate the retinal
function in patients with AZOOR.9,42,310,320 Arai et
al showed that mfERG responses were recordable
only in the central retinal areas in a patient with
AZOOR, which corresponded with the perimetry
findings.9 Yasuda et al also evaluated the role of
mfERG in serial monitoring of visual function in
a patient with AZOOR.320 It was found that there
was delayed recovery in mfERG response as com-
pared with changes in visual acuity and perimetry.
mfERG also demonstrated persistent retinal dys-
function after resolution of AZOOR clinically as
subnormal first- and second-order mfERG responses
were found in a patient 4 years after onset of
bilateral AZOOR.310 The mfERG abnormalities also
extended beyond the areas of visual field defects in
both eyes. The use of mfERG allowed the topo-
graphic assessment of retinal function in patients
with AZOOR.
APPLICATIONS OF MULTIFOCAL ELECTRORETINOGRAPHY 77

Fig. 8. mfERG findings in a patient after blunt trauma. Top Left: Fundus photograph of demonstrating commotio retinae
and traumatic macular hole. Top Right: Mid-phase fluorescence angiography of the patient demonstrating areas of
hyperfluorescence at the site of commotio retinae and at the macular hole. Bottom Left: mfERG trace array showing
reduction of mfERG response at the fovea with a localized area of abnormal mfERG responses at the superionasal retina.
Bottom Right: Three-dimensional topography showing reduction of the foveal peak response density and a well-
demarcated area of reduced response density due to commotio retinae.

Acute Macular Neuroretinopathy (AMN)
Acute macular neuroretinopathy (AMN) is a rare
condition that results in sudden onset of paracentral
scotoma without usually affecting the visual acuity.
Clinically, reddish brown deep macular lesions may
be observed and fluorescein angiography findings
are usually normal. mfERG has been used to
objectively demonstrate the extent of retinal dys-
function in patients with AMN and patients were
found to have localized areas of retinal dysfunction
which corresponded to the scotoma.22,33,191,309 The
area of depressed retinal response may also be more
diffuse compared with the scotoma, suggesting
more diffuse retinal dysfunction can occur in
patients with AMN.191 mfERG also detected sub-
clinical retinal dysfunction in the asymptomatic
fellow eye of a patient with AMN.309 The mfERG
findings indicated that AMN is a disease that affects
mainly the outer retina at the photoreceptor or
bipolar cell levels.22,191 Because AMN patients may
have relatively small scotoma, stimulus pattern with
103 or more hexagons should be used for recording
as the 61-hexagon stimulus was unable to detect
localized functional abnormality in a patient with
AMN.59
Acute Idiopathic Blind Spot Enlargement
Syndrome (AIBSE)
Acute idiopathic blind spot enlargement syn-
drome (AIBSE) is a disease characterized by
enlarged blind spot without visible changes in the
optic disc and the peripapillary retina. The disease is
78 Surv Ophthalmol 52 (1) January--February 2007 LAI ET AL

Fig. 9. mfERG findings in a patient with multifocal evanescent white dot syndrome (MEWDS). Top, Left and Right:
Fundus photographs demonstrating the characteristic features of MEWDS with foveal granularity and multiple fine white
dots at the level of retinal pigment epithelium in the mid-periphery. Bottom, Left and Right: Trace array and three-
dimensional topography of mfERG responses demonstrating an area of reduced responses extending from the blind spot
which corresponded well with the enlarged blind spot reported by the patient.

thought to be caused by peripapillary chorioretinal
dysfunction and is diagnosed after excluding other
conditions, such as MEWDS, AZOOR, and MFC.310
Patients usually develop temporal visual field loss
with normal visual acuity. mfERG has been shown to
be useful in the evaluation of retinal dysfunction in
patients with AIBSE.62,145,180,310 Fletcher et al
reported the use of a prototype mfERG in patients
with AIBSE and loss of waveforms were found in
retinal areas surrounding the optic disk.62 Kondo et
al also reported abnormal mfERG responses in areas
corresponding to scotoma in patients with AIBSE.145
The mfERG abnormality in the nasal retina
persisted three months later despite resolution of
symptoms clinically and mfERG enabled the de-
tection of subclinical retinal dysfunction in the
patient. The mfERG findings confirmed retinal
dysfunction as the main abnormality in this syn-
drome.
Antienolase Retinopathy and
Melanoma-associated Retinopathy (MAR)
Autoimmune retinopathy can occur due to
antibodies directed to retinal proteins and may be
a paraneoplastic condition. mfERG has been dem-
onstrated to be useful in assessing the retinal
function of patients with antienolase retinopathy
and melanoma-associated retinopathy (MAR).226,312
Weleber et al demonstrated that patients with early
antienolase retinopathy may develop central cone
dysfunction only evident on mfERG.312 mfERG has
APPLICATIONS OF MULTIFOCAL ELECTRORETINOGRAPHY
also been used to assess retinal dysfunction in
a patient with MAR and improvement in mfERG
response amplitude of the central macula was
observed after treatment of metastasis.226
Purtscher-like Retinopathy
Purtscher-like retinopathy is characterized by
sudden loss of vision with bilateral or unilateral
patches of retinal whitening and hemorrhages in
the posterior pole without a history of trauma. Haq
et al performed mfERG in a patient with pancrea-
titis-associated Purtscher-like retinopathy.85 It was
found that there were reductions in both N1 and P1
amplitudes and this suggested that the outer retinal
layers are affected in Purtscher-like retinopathy. This
is in contrast with the common belief that Purtscher-
like retinopathy mainly causes changes in the inner
retina. The mfERG findings demonstrated that the
outer retina is also damaged in Purtscher-like
retinopathy, which may be secondary to infarctions
of the choriocapillaries.
Pre-eclampsia and Choroidal Ischemia
Patients with pre-eclampsia may develop transient
vasospasm in choroidal circulation, resulting in
choroidal ischemia and serous retinal detachment.
Kwok et al performed serial mfERG in a patient with
visual loss due to choroidal ischemia associated with
pre-eclampsia.159 Persistent reductions in response
amplitude were found despite recovery in visual
acuity and fluorescein and indocyanine green
angiographies. mfERG allowed documentation of
retinal dysfunction due to choroidal ischemia and
was more sensitive compared with fundus angiogra-
phy in demonstrating the retinal abnormalities.
Vogt-Koyanagi-Harada Disease
Vogt-Koyanagi-Harada (VKH) disease is a bilateral
granulomatous panuveitis that may result in visual
loss due to generalized retinal atrophy caused by
inflammation or exudative retinal detachment.
Chee et al performed mfERG to investigate the
visual function deficits in patients with convalescent
VKH.36 It was demonstrated that mfERG response
amplitudes were significantly reduced with delays in
implicit times throughout the macula in patients
with large area of peripapillary atrophy (O2 disk
areas). Patients with smaller area of peripapillary
atrophy (!1 disk area) were also found to have
reduced mfERG amplitude throughout the entire
macula with delayed implicit times in the peripapil-
lary region. These mfERG findings showed that
retinal functional impairment can occur in VKH
patients with normal visual acuity and no apparent
retinal atrophy.
79
Miscellaneous Acquired Retinal Conditions
mfERG has been used in the assessment of
localized retinal dysfunction in uncommon diseases
such as unilateral acute idiopathic maculopathy
(UAIM),3,213 idiopathic unilateral bull’s eye macul-
opathy,215 and high-altitude hypobaric hypoxic
maculopathy.233 mfERG allowed topographic analy-
sis of retinal dysfunction and monitoring of the
disease process in these cases. In a patient with
pseudotumor cerebri, mfERG has also demon-
strated that in addition to optic nerve damage, the
visual loss may also be caused by central retinal
damage as a result of long-standing retinal
edema.124
Clinical Applications of mfERG in
Hereditary and Congenital Retinal
Diseases
STARGARDT MACULAR DYSTROPHY AND FUNDUS
FLAVIMACULATUS
Stargardt macular dystrophy (SMD) and fundus
flavimaculatus (FF) are hereditary diseases charac-
terized by progressive visual loss in the first or
second decades of life with progressive atrophy of
the macula. Because the functional loss is initially
limited to the macular region, full-field ERG and
electro-oculography (EOG) are not useful in detect-
ing early stages of SMD and FF. mfERG has been
shown to be useful in documenting foveal dysfunc-
tion in patients with these disor-
ders.52,70,149,150,153,253 Kretschmann et al showed
that 49 of 51 patients with SMD had severe
reduction in mfERG response amplitudes in the
central 5 of the retina.153 Slight but significant
increases in implicit times were also observed
compared with normal controls. In another study
by Gerth et al, all SMD patients were found to have
markedly reduced mfERG response amplitude and
most had delayed implicit times.70 In order to
evaluate the correlation between the areas of retinal
dysfunction and scotoma in SMD patients, Rudolph
et al analyzed the mfERG obtained from SLO
stimulus and compared with the SLO microperim-
etry findings.253 Area of reduced retinal function
detected by mfERG using SLO stimulus correlated
well with the size of scotoma detected on SLO
microperimetry. These findings suggested that
mfERG is useful in detecting central retinal dys-
function in SMD and is especially useful in patients
with minimal fundus changes in which the diagnosis
of SMD may be difficult.
80 Surv Ophthalmol 52 (1) January--February 2007
RETINITIS PIGMENTOSA / ROD--CONE
DYSTROPHY
Retinitis pigmentosa (RP) is a diverse group of
hereditary and sporadic disorders characterized by
dysfunctions of photoreceptors and RPE. Because
rod functions are usually impaired earlier and more
severe than cone functions, RP is also known as rod--
cone dystrophy. Conventional full-field ERG is used
in the diagnosis of RP and patients may have
severely abnormal or non-detectable scotopic ERG.
As full-field ERG measures the mass response of the
retina, it is unable to assess the central retinal
function specifically. mfERG has been widely
utilized to evaluate the central and regional
variations of retinal dysfunction in RP pa-
tients.29,47,61,77,92,98,140,146,248,265,272,304,321 mfERG is
helpful in differentiating between affected and
unaffected retinal areas and both amplitude and
implicit time abnormalities were found to be
dependent on retinal eccentricities.272 RP patients
were found to have significant reductions in re-
sponse amplitudes at all retinal eccentricities and
implicit times were generally within normal in the
central areas but became significantly delayed
towards the peripheral retina.29,61,98,272,274 In pa-
tients with advanced RP, it is often difficult to detect
full-field ERG waveform despite only slight reduc-
tion in visual acuity. mfERG is useful in demonstrat-
ing small residual central retinal function that might
be preserved in these patients.77,92
Using special parameters, Holopigian et al stud-
ied both the cone-mediated and rod-mediated
mfERG in RP patients.92 Results demonstrated that
whereas the cone-mediated mfERG response ampli-
tudes and implicit times had significant correlations
with the extent of visual field loss, the rod-mediated
mfERG findings showed no correlation. This find-
ing suggests that dysfunction of cone and rod
systems may develop independently in RP patients.
In another study by Hood et al, only implicit time
changes but not amplitude changes were found to
be correlated with the locations of visual field
sensitivity loss.98 mfERG implicit time measure-
ments are therefore more important than ampli-
tudes parameters in assessing the location of retinal
dysfunction in patients with early RP.
mfERG is also useful in the assessment of central
retinal dysfunction in patients with various subtypes
of RP such as sector RP,223,270,321 Usher syndrome
(US),272,276 and Bietti crystalline retinopathy.119,121
Patients with sector RP may have subnormal
scotopic ERG with normal photopic ERG.223,270,321
The mfERG abnormalities generally correspond
well with the visual field and morphological find-
ings.223,270,321 Locations without visible RP pigmen-
LAI ET AL
tary changes may also exhibit abnormal mfERG
responses due to more diffuse area of functional
loss.321 mfERG enabled the topographic assessment
of retinal function in patients with various subtypes
of US. Seeliger et al found that while US type II and
RP patients had significant delays in mfERG implicit
times, US type I patients had no or only mild delay
in implicit times.276 The differences in mfERG
implicit times between US types I and II patients
were most marked in the peripheral areas. Analysis
of mfERG implicit times can therefore assist the
differentiation of subtypes of US, which goes along
with differences in the degree of sensorineural
hearing loss, and has important clinical significance
as US types I and II are associated with different
severity of sensorineural hearing loss.
mfERG has also been performed to map the
localized retinal dysfunction in carriers of X-linked
RP.304 Vajaranant et al demonstrated localized
mosaic pattern of mfERG abnormalities may be
present in X-linked RP carriers, including a patient
with normal visual field, full-field photopic ERG, and
clinical findings.304 mfERG can therefore provide an
objective measurement of retinal function to study
the phenotype of various genetic expressions in RP.
Because conventional mfERG can only record the
responses from the central 50--60 of the retina,
retinal dysfunction might not be detected in early
stages of RP if it is limited to the peripheral retina.
This can be overcome with the use of WF-mfERG,
which allows the detection of early retinitis pigmen-
tosa with more peripheral retinal dysfunction.49
CONE DYSTROPHY AND OCCULT MACULAR
DYSTROPHY
Cone dystrophy is an inherited retinal disorder
that predominantly affects the cone system, whereas
rod system function is mostly preserved. Patients
with cone dystrophy are characterized by reduced
visual acuity, abnormal color vision, and photopho-
bia. Diagnosis of cone dystrophy is usually made by
reduction of photopic full-field ERG and relatively
normal scotopic ERG. Because mfERG can provide
an objective measurement of central cone function,
it is particularly useful in the assessment of cone
dystrophy.80,93,131,149,152,154,169,282 The main mfERG
findings in patients with cone dystrophy include
severe reductions in response amplitudes with
delays in implicit times or complete absence of
mfERG responses, especially in the central ret-
ina.93,131,152,154,169,282 Holopigian et al evaluated
both the cone- and rod-mediated mfERG in patients
with cone dystrophy.93 It was shown that patients
had large reductions in cone-mediated mfERG
APPLICATIONS OF MULTIFOCAL ELECTRORETINOGRAPHY
amplitude and delays in implicit time which were
more marked in the central retina. The abnormal-
ities in cone-mediated mfERG were more diffuse
compared with the visual field defects. For the rod-
mediated mfERG, the amplitudes and implicit times
were within normal limits in most patients. Green-
stein et al also demonstrated that patients with cone
dystrophy had marked reduction in second-order
kernel responses in areas of decreased visual field
sensitivity.80 This suggests that in addition to cone
photoreceptor damage, there may be associated
outer plexiform layer damage in cone dystrophy.
The topographic assessment of mfERG has
further enabled the classification of cone dystrophy
into peripheral and central types. The peripheral
type of cone dystrophy was reported by Kondo et al
in which mfERG demonstrated a predominant
dysfunction in the peripheral cone with relatively
preserved central cone function.142 The central type
of cone dystrophy is also known as occult macular
dystrophy (OMD) and is characterized by progres-
sive visual loss with normal fundus appearance and
fluorescein angiography. Patients with OMD have
normal full-field ERG but the focal macular cone
ERG is abnormal. Because the retinal dysfunction is
only localized to the macula, mfERG is very useful in
the diagnosis of OMD.68,112,212,236,269,314,328 The
characteristic mfERG abnormalities in OMD include
marked reductions in P1 response amplitudes in the
central macula and minimal reduction towards the
peripheral macula.236,314 There are also slight but
significant delays in P1 implicit times over the entire
macular region. Because patients with OMD do not
have visible fundus morphology, mfERG can allow
detection of localized foveal cone dysfunction and
differentiate OMD from functional visual loss.112
Moreover, as focal macular ERG are more time-
consuming to perform compared with mfERG,
mfERG is the investigation of choice in diagnosing
patients with OMD.
BEST DISEASE AND ADULT ONSET VITELLIFORM
MACULAR DYSTROPHY
Best disease is an autosomal dominant progressive
macular dystrophy associated with juvenile-onset of
visual loss. An adult-onset form of the disease has
also been identified and is known as adult onset
vitelliform macular dystrophy (AVMD). Both dis-
eases are due to different phenotype expressions
caused by mutation of the VMD2 gene. The disease
is a generalized disorder of the RPE causing
excessive accumulation of lipofuscin, resulting in
the characteristic egg-yolk macular lesions in later
stages of the disease. EOG is typically abnormal in
patients with Best disease but may be within normal
81
range in AVMD. Because these diseases predomi-
nantly affect the macula, mfERG is useful in the
assessment of retinal function in patients with Best
disease and AVMD.51,224,246,247,250,259,271 Most stud-
ies have demonstrated that the majority of patients
with Best disease and AVMD have reduced P1
amplitude in the central 5--10 of the retina with
sparing of peripheral response ampli-
tudes.71,224,246,247,250,271 The mfERG implicit times
are generally not affected in most patients. Saito et
al reported generalized reductions in response
amplitudes throughout the macula in 92% of
patients with AVMD, suggesting the impairment in
retinal function is not only limited to the central
macula.259 However, the generalized reduction in
mfERG responses was only seen in 14% of eyes in
the study by Renner et al and these findings may
suggest a large variability in the extent of retinal
dysfunction in AVMD.247 Scholl et al also demon-
strated that mfERG amplitude significantly corre-
lated with visual acuity and the stage of disease.271
Because mfERG abnormalities are often detected in
Best disease and AVMD patients with good visual
acuity, mfERG may serve as an indicator of the
extent of retinal functional impairment in these
patients.
CENTRAL AREOLAR CHOROIDAL DYSTROPHY
Central areolar choroidal dystrophy (CACD) is
a macular dystrophy that may be sporadic or
hereditary. It is characterized by the presence of
bilateral symmetric round areas of well-demarcated
choroidal, RPE, and retinal atrophy. Because CACD
affects only the macula, full-field ERG is usually
normal and is not useful in assessing patients with
CACD particularly in the early stage. Several studies
have evaluated the use of mfERG in patients with
early and advanced stages of CACD.60,87,129,211
Patients with advanced CACD were found to have
significant reductions in P1 amplitudes in the
central macula compared with controls.60,87,129
mfERG allowed the documentation of localized
retinal dysfunction that could not be detected by
full-field ERG. Nagasaka et al studied both the first-
and second-order mfERG responses in patients with
early CACD.211 Patients were found to have reduced
first-order amplitude in the atrophic areas as well as
the clinically normal areas, suggesting more diffuse
impairment of retinal function as compared with
the morphological changes. Although second-order
kernels responses were also severely reduced, the
ratios of second-order to first-order kernel ampli-
tudes were relatively normal in areas free of atrophic
changes. These findings suggest that the cause of
retinal dysfunction in CACD is likely to be
82 Surv Ophthalmol 52 (1) January--February 2007
pre-synaptic to the bipolar cells. The use of mfERG
has improved the understanding of the pathophys-
iology in CACD.
CHOROIDEREMIA
Choroideremia is an X-linked hereditary disease
causing progressive degeneration of the RPE,
choriocapillaries, and retina. mfERG has been used
to assess retinal dysfunction in affected individuals
as well as female carriers of choroideremia.43,254
Rudolph et al performed mfERG in an affected
patient and two female carriers of choroideremia.254
In the affected patient, only a small mfERG re-
sponse was recordable in the central fovea and
waveforms were not recordable across the posterior
pole, indicative of severe impairment in macular
function. Reduced mfERG responses were also
found in asymptomatic carriers of choroideremia.
mfERG can therefore be utilized in the detection of
functional abnormalities in carriers of choroider-
emia.
CONGENITAL STATIONARY NIGHT BLINDNESS
Congenital stationary night blindness (CSNB) is
a non-progressive retinal disorder characterized by
night blindness, moderately reduced visual acuity,
and myopia. The underlying defect in CSNB is
thought to be due to defects in the neurotransmis-
sion from rod photoreceptors to on-bipolar cells.
Kondo et al performed mfERG in patients with
complete type of CSNB to assess the retinal origins
of each mfERG component.141 For the first-order
kernel response, the response amplitudes were
found to be normal in CSNB patients whereas the
implicit times were delayed. CSNB patients also had
severely reduced or absent second-order responses
due to abnormality in the postsynaptic on-pathway
and this led to subsequent delay in implicit times for
the first-order kernel response. These findings
emphasized the importance of measuring mfERG
implicit times as patients with CSNB commonly had
normal fundus findings and the diagnosis of CSNB
may be missed if only mfERG amplitudes were
analyzed. mfERG has also been performed in
patients with Oguchi disease, a rare form of
CSNB.322 The mfERG was found to be within
normal limit as the disease predominately affects
the rod. The results showed that the central cone
functions are relatively preserved in Oguchi disease
and is consistent with the finding of normal S-cone
ERG in patients with Oguchi disease.
X-LINKED RETINOSCHISIS
X-linked retinoschisis (XLRS) is a bilateral he-
reditary vitreoretinal dystrophy due to mutation of
LAI ET AL
the RS1 gene. XLRS is characterized by microcystic
changes at the macula, resulting in visual loss in
young men. Patients with XLRS have abnormal
scotopic full-field ERG with the characteristic
negative waveform due to selective reduction of
the b-wave. mfERG has been performed in detecting
localized macular dysfunction in patients with XLRS
and patients were found to have significantly
reduced P1 response amplitude in the central
macula.109,207,235 Muscat et al demonstrated that
mfERG is a very sensitive tool in XLRS which
enabled detection of localized retinal dysfunction
in a patient who had normal full-field ERG in one
eye.207 Piao et al found that some patients with
XLRS also exhibited large reductions in mfERG
amplitudes outside the fovea with significant delays
in first-order implicit times in all retinal locations.235
Second-order kernel analysis also showed absence of
waveform and the ratio of amplitudes of the second-
order kernel to the first-order kernel was signifi-
cantly reduced. The findings suggested that XLRS
caused inner retinal impairment and resulted in
wide-spread cone-system dysfunction.
ACHROMATOPSIA
Complete achromatopsia or rod monochromacy
is a rare autosomal recessively inherited disease that
causes severe visual loss and total color blindness.
Patients with achromatopsia have absence of cone
function and normal rod function. A subgroup of
patient may have preserved S-cone and the condi-
tion is known as blue-cone monochromacy. mfERG
in both types of achromatopsia showed no signifi-
cant waveform recorded from the entire macula as
the mfERG is mainly cone-driven.53
ENHANCED S-CONE SYNDROME
Enhanced S-cone syndrome (ESCS) is a rare
hereditary retinal disorder characterized by the
absence of rod function and large-amplitude
S-cone-mediated responses in photopic full-field
ERG. mfERG has been used to assess the topo-
graphic distribution of the neural connections in
patients with ESCS. Marmor et al reported the
mfERG findings in a patient with ESCS and it was
found that the mfERG responses consisted mostly of
monophasic negative waveforms except near the
central macula.186 Ring analysis showed moderate
delays in N1 and P1 implicit times in the central
fovea. However in the peripheral macula, there were
marked prolongations of N1 waveform with a very
slow P1 peak at around 60 msec. Using colored
stimulation, it was further demonstrated that ESCS
patient had twice the normal amplitude to blue
stimulus with normal amplitude to red stimulus.
APPLICATIONS OF MULTIFOCAL ELECTRORETINOGRAPHY
Recording of multifocal off-responses also showed
lack of off-response beyond the central 7 of the
macula. These results demonstrated marked differ-
ences between the central and peripheral mfERG
responses and indicated that S-cones may feed into
different neural pathways in different retinal
regions.
KJELLIN SYNDROME
Kjellin syndrome is an autosomal recessive disease
characterized by spastic paraplegia, mental retarda-
tion, amyotrophia, and central retinal degeneration.
mfERG has been shown to be useful in detecting the
central retinal dysfunction in a patient with Kjellin
syndrome who had normal EOG and full-field ERG
findings.67
MATERNAL INHERITED DIABETES AND DEAFNESS
Maternal inherited diabetes and deafness (MIDD)
is a mitochondrial inherited disease characterized
by diabetes mellitus, neurosensory hearing loss, and
retinal dystrophy. The fundus changes mainly in-
volve the posterior pole and can range from mild
abnormal pigmentation to extensive RPE atrophy.
Because most patients had normal full-field ERG
due to relatively intact gross retinal function,
mfERG has been used to evaluate the central retinal
function in patients with MIDD.17 Patients were
found to have reduced mfERG amplitudes with
normal implicit times and in one MIDD patient,
mfERG showed reduced P1 amplitude at the central
macula despite normal pattern ERG. By analyzing
responses from different retinal locations, mfERG
was more sensitive in detecting subtle changes in
macular function compared with pattern ERG. The
locations of mfERG abnormalities also corre-
sponded well with areas of the characteristic fundus
autofluorescence abnormalities present in MIDD.
The findings suggested the localized retinal dys-
function in MIDD is caused by loss of cone
photoreceptor outer segment and RPE dysfunction.
OTHER HEREDITARY RETINAL DISEASES
mfERG has also been used to demonstrate
impairments in central and paracentral retinal
functions in patients with other retinal dystrophies,
such as malattia leventinese,69 fundus albipuncta-
tus,257 Bothnia dystrophy,75 and retinal diseases
caused by various genetic defects, such as mutation
of the serum retinol blinding protein gene,273
mutation of the peripherin/RDS gene,263 and
trinucleotide repeat expansion of the spinocerebel-
lar ataxis type 7 (SCA7) gene.1
83
Clinical Applications of mfERG
in the Monitoring of Treatment for
Retinal Diseases
PHOTODYNAMIC THERAPY
Photodynamic therapy (PDT) with verteporfin has
been demonstrated by randomized control trials to
be effective in the treatment of subfoveal choroidal
neovascularization (CNV) due to AMD and patho-
logic myopia. Several studies have used mfERG to
provide an objective assessment of the changes in
retinal function after PDT.118,147,161,203,205,220,256
Palmowski et al demonstrated that there were
improvements in parafoveal mfERG responses after
PDT for CNV due to AMD.220 In another study by
Moschos et al, mfERG was performed in patients who
had PDT for myopic CNV and it was similarly shown
that mfERG response densities increased after
PDT.205 However, in patients who had PDT for CNV
due to AMD, there were reductions in the mean
retinal response densities in the foveal and parafoveal
areas 6 months after PDT.203 Rüther et al found
a general reduction in P1 response amplitude and
delay in implicit time after a median interval of
6 weeks post-PDT but the differences were not
statistically significant.256 These studies showed that
various forms of macular functional changes can
occur in patients who had PDT for CNV.
One of the side effects after PDT is the de-
velopment of transient visual disturbances shortly
after treatment. It is often difficult to detect these
subtle non-specific changes objectively with visual
acuity testing alone. mfERG has been performed to
investigate the short-term changes in macular
function after PDT. Jiang et al evaluated the mfERG
findings at 3 and 7 days in patients who had PDT for
CNV.118 It was shown that with exception of the
statistically significant delay in N1 implicit time for
ring 5 at 7 days post-PDT, no other significant
changes were observed. In another study by Lai et al,
there were significant reductions in the mean N1
and P1 response amplitudes and delays in implicit
times within 2 weeks after PDT.161 The mfERG
amplitudes and implicit times returned to pre-PDT
level at 1 month after treatment. These mfERG
findings may explain the early subjective visual
disturbances after PDT in the presence of normal
clinical findings.
RETINAL SURGERY
Macular Hole and Epiretinal Membrane
As described in previous sections, mfERG has
been shown to be useful in providing objective
assessment of the preoperative and postoperative
84 Surv Ophthalmol 52 (1) January--February 2007
macular function in patients undergoing macular
hole and ERM surgeries.7,10,106,200,201,216,283 mfERG
has also been used to evaluate the potential retinal
damage associated with macular hole and ERM
surgery.10,106,216,311
Retinal Detachment
mfERG has been used to investigate the changes
in retinal function before and after retinal de-
tachment surgery.202,262,316 mfERG has the advan-
tage compared with full-field ERG because it allows
separate assessment of retinal function between the
attached and detached retina. Sasoh et al evaluated
the preoperative and postoperative changes in
mfERG and visual field in patients who had retinal
detachment surgery.262 Preoperatively, patients had
marked reduction in response density in the area of
detached retina. Mild reduction in response density
was also noted in the attached retinal area. Surgery
resulted in less recovery in response density com-
pared with visual field sensitivity. The mfERG
implicit time however was not assessed in the study.
In another study by Wu et al, it was found that
retinal detachment surgery resulted in significant
improvements in both the N1 and P1 response
densities.316 There were also slight decreases in
implicit times but the changes were not statistically
significant. Cazabon et al also reported the use of
mfERG in evaluating unexplained visual loss after
silicone oil removal in three patients who had
vitrectomies for retinal detachment.25 mfERG dem-
onstrated reduced response at the central macula
which correlated with the reduction in pattern
electroretinogram amplitude, suggestive of macular
dysfunction. The exact mechanism of visual loss
however remained uncertain.
Optic Disk Pit
Optic disk pit may result in visual loss due to
serous macular detachment, and macular buckling
has been proposed as a treatment option. Theodos-
siadis et al used mfERG for the preoperative and
postoperative assessments in patients undergoing
macular buckling surgery for serous macular de-
tachment caused by optic disk pit.300 Preoperatively,
patients had reduced foveal and parafoveal response
densities as a result of the macular detachment.
After successful surgery, all patients had improve-
ment in response densities and mfERG thus pro-
vided an objective measure of macular function in
these patients.
LAI ET AL
Arteriovenous Decompression and Radial Optic
Neurotomy for Retinal Vein Occlusion
Patients with BRVO or CRVO may develop visual
loss due to macular edema, hemorrhage or ische-
mia. Treatment with laser photocoagulation may not
be effective in BRVO and vitrectomy with arteriove-
nous decompression has been proposed as an
alterative treatment option. mfERG has been
applied to assess the preoperative and postoperative
macular function in BRVO patients who underwent
arteriovenous decompression surgery.171,196 Mester
and Dillinger reported improvement in mfERG
responses in 7 patients who had vitrectomy with
arteriovenous decompression but the details of the
mfERG response amplitudes and implicit times
findings were not reported.196 Lu et al also showed
that there were improvements in both the central
and peripheral retinal response densities after
arteriovenous adventitial sheathotomy for BRVO.171
For patients with ischemic CRVO, mfERG has also
been used to evaluate the retinal functional changes
following radial optic neurotomy (RON).189 It was
shown that RON did not improve visual function in
terms of mfERG changes despite a reduction in
macular thickness. mfERG can therefore provide an
alternative measure of macular function in addi-
tional to other traditional outcome such as visual
acuity and fluorescein angiography.
Retinal transplantation
Retinal transplantation with RPE and/or retina
has been proposed for the treatment of diseases
such as RP and AMD. mfERG was used to determine
the electrophysiological changes at the transplanta-
tion site after surgery.243--245 Radtke et al reported
the presence of transient mfERG responses at the
transplantation site in a RP patient who had
undergone retinal sheet transplantation.243 How-
ever, in subsequent studies, no changes in mfERG
recordings were detected after retinal transplanta-
tion despite one patient who developed visual
improvement.244,245 The poor preoperative visual
acuity of light perception in most patients might
have accounted for the lack of mfERG changes.245
Another reason may also be due to the inability of
mfERG to extract clear signals from the retinal
transplantation site due to poor signal-to-noise
ratio.244 Future refinement in the technical param-
eters of mfERG may enable its application in
assessing the efficacy of retinal transplantation
objectively.
mfERG has also been used to assess the retinal
function after transplantation of autologous RPE
cells in patients with subfoveal CNV due to AMD.2,19
Abri et al demonstrated that there was good
APPLICATIONS OF MULTIFOCAL ELECTRORETINOGRAPHY
correlation between visual acuity and mfERG
findings in patients who had autologous RPE cell
transplantation.2 Binder et al also showed that
patients who underwent combined subretinal mem-
brane excision with simultaneous transplantation of
autologous RPE cells had significantly higher
mfERG responses than patients who had membrane
removal alone.19 These results suggested that
mfERG is a useful tool for the objective assessment
of retinal function after autologous RPE cell trans-
plantation.
Focal laser and pan-retinal photocoagulation
Focal laser photocoagulation is commonly per-
formed for the treatment of various macular
disorders such as macular edema caused by diabetic
retinopathy and BRVO. Greenstein et al used sf-
mfERG to assess the effects of focal laser photoco-
agulation in patients with diabetic macular edema.78
Most patients had no change in terms of visual
acuity and visual field sensitivity. However, mfERG
showed that patients had reduced amplitude and
increased implicit times at 8 to 12 weeks after laser
treatment. Timing measures were more affected
compared with amplitude changes and the impair-
ment in mfERG responses also extended beyond the
area of laser photocoagulation. The findings sug-
gested that although no change was found in terms
of visual acuity, mfERG demonstrated that laser
photocoagulation for diabetic macular edema might
result in some retinal damage caused by laser energy
or due to generalized alteration in retinal metabo-
lism. Martidis et al also applied mfERG to investigate
the effects of laser photocoagulation for the
treatment of subretinal nematode.188 Despite the
patient having an initial visual acuity of 20/20, pre-
laser mfERG demonstrated decreased mfERG re-
sponse amplitude at the fovea due to retinal toxicity
caused by the worm. Successful laser treatment of
the worm resulted in recovery of both the foveal and
perifoveal response amplitudes.
Lövestam-Adrian et al also evaluated the macular
function using mfERG before and after pan-retinal
photocoagulation (PRP) for proliferative diabetic
retinopathy.170 It was found that although there
were no significant changes in visual acuity and
macular thickness on OCT, there were significant
reductions in mfERG response amplitudes of the
central rings at 6 months after PRP. The finding
suggested retinal functional impairment may occur
in the untreated macula following PRP.
Others
mfERG has been applied to investigate the
changes in retinal function after interferon a2a
85
treatment for patients with ocular Behcet disease.287
Stübiger et al demonstrated reduction in central
mfERG response amplitudes in patients with ocular
Behcet disease due to macular edema or secondary
atrophic changes.287 Delayed P1 implicit times were
also observed in patients with severe recurrent
uveitis. After treatment with interferon alpha-2a,
the response amplitudes improved in patients with
macular edema and the implicit times normalized in
patients without chronic atrophic changes. The
mfERG findings had no correlation with visual
acuity but appeared to correlate well with the
duration and severity of ocular diseases.
Shimada and Horiguchi have also used mfERG to
assess the retinal function after transpupillary
thermotherapy (TTT) for treating subfoveal
CNV.280 Results demonstrated significant reduction
in the P1 response amplitude within the first minute
after TTT. There was also significant prolongation of
P1 implicit time at 15 minutes then at 24 hours and
7 days after TTT. The mfERG abnormalities were
possibly due to an early thermal effect, followed by
other physiological responses. In another study by
Ladewig et al, mfERG was performed to investigate
the retinal functional changes after prostaglandin
E1 infusion for the treatment of dry AMD.160 It was
demonstrated that post-treatment mfERG response
amplitude increased by 20% in 3 patients, un-
changed in 2 patients, and reduced by 10% in 2
patients. Because no statistical analysis was carried
out, the extent of mfERG changes after treatment
remained uncertain. Luu et al also carried out
mfERG to evaluate the retinal functional changes in
children receiving atropine eye drops for myopia
and mfERG showed no significant changes in retinal
function after 2 years of treatment.176
Clinical Applications of mfERG
in Glaucoma, Ocular Hypertension,
and Optic Neuropathy
PRIMARY OPEN-ANGLE GLAUCOMA
Primary open-angle glaucoma (POAG) is a com-
mon cause of visual impairment, and perimetry is
the most commonly used method in the diagnosis
and monitoring of glaucomatous damage. One of
the main limitations of perimetry is the subjective
nature of the assessment and therefore false positive
and negative results are not uncommon. In view of
the ability of mfERG to objectively measure retinal
responses topographically, studies have attempted to
use mfERG to evaluate the functional changes in
glaucoma.26,28,64,89,97,221,227,260,306 Chan and Brown
showed that glaucoma patients had significant
reductions in both the first- and second-order
86 Surv Ophthalmol 52 (1) January--February 2007
kernel response amplitudes compared with con-
trol.28 However, it was unclear whether the mfERG
findings were representative of the visual field
defects as no correlation analysis with visual field
findings was performed in the study. Hasegawa et al
evaluated the relationship between changes in first-
order kernel mfERG responses and visual field loss
in patients with glaucoma.89 It was shown that
POAG patients had small but significant changes in
P1 and N2 implicit times compared with control.
However, there were no significant differences in
response amplitudes between the POAG and con-
trol groups. The implicit times but not response
amplitudes correlated with mean sensitivity values of
static perimetry. Similarly, Hood et al also found
significantly longer mean P1 implicit times in
patients with glaucoma compared with control but
some patients still had normal implicit times despite
visual severe field loss.97 Using a 50% low-contrast
stimulus instead of the conventional mfERG stimu-
lus, Chan showed that the oscillatory component on
the descending limb of the first-order kernel
response was reduced in two patients with POAG.26
The reduction in the oscillatory component also
correlated with the quadrant with glaucomatous
visual field loss.26 In another study by Fortune et al,
there were no significant differences between the
response densities from the affected and relatively
unaffected hemifields and this finding suggested
a lack of spatial correspondence between mfERG
and visual field findings.64 Palmowski et al also
demonstrated that despite significant delays in
mfERG implicit times in the glaucoma group,
overlaps of response parameters exist between the
control and POAG patients.221 These results implied
that mfERG is not very reliable in the detection and
monitoring of functional loss caused by glaucoma.
Studies have also evaluated the role of second-
order kernel mfERG responses in the assessment of
glaucoma. Hood et al showed that there was no
significant difference between the amplitude ratio
of the second-order to the first-order response in
glaucoma patients compared with control.97 In
another study by Sakemi et al, it was demonstrated
that neither first- nor second-order kernel mfERG
response showed changes that reflected early
glaucomatous visual field defects.260 Palmowski et
al also showed that although there was significant
correlation between second-order mfERG response
and visual field findings, the serial changes were
small over time and mfERG was not sensitive
enough in assessing functional changes in POAG.227
These results suggested that although changes in
second-order kernel responses are due to abnor-
mality in adaptation mechanisms of the inner
retina, retinal ganglion cells are not necessarily
LAI ET AL
damaged in the process of second-order response
abnormality and thus is not very useful in
investigating glaucomatous damage.104
In view of studies demonstrating the lack of
sensitivity in both the first- and second-order mfERG
components in the assessment of glaucoma, further
research was performed to investigate the role of
specific mfERG components in the evaluation of
glaucomatous damage. Hood et al analyzed the
mfERG amplitude component at 8.3 msec after the
first-order P1 peak to evaluate the inner retinal
damage of the ganglion cells caused by glaucoma.97
This component is suggested to be contributed by
the inner retina in monkeys after blockage of retinal
ganglion cell potentials by TTX and NMDA.95,96
Ratio measures were calculated by dividing the
amplitude at 8.3 msec after P1 by the P1 amplitude.
Results showed that although the mean ratio was
significantly lower in glaucoma patients compared
with control, only 33% of patients had reduced
ratios outside the normal range and therefore this
parameter was not sensitive enough to detect
glaucomatous changes. Studies have also evaluated
a similar wavelet on the descending limb of the first-
order P1 mfERG response called s-wave which was
suggested to be useful in the assessment of
glaucoma.137,206 The s-wave can be enhanced using
a low-frequency mfERG stimulus and the response is
thought to arise from the retinal ganglion cells as it
is significantly higher in amplitude at locations
closer to the optic nerve and is absent in patients
with optic neuritis.261 Studies by Murai et al and
Kobayashi et al showed that the s-wave amplitudes
were significantly smaller in glaucoma patients
compared with control.137,206 Analysis also demon-
strated significant correlation between the s-wave
mfERG amplitude and visual field sensitivity.206
However, the analysis was only done by hemifield
and it was unclear whether good correlations exist
between the s-wave parameters and visual field
sensitivity for specific retinal locations. Therefore
the use of mfERG s-wave in assessing glaucomatous
damage remained uncertain.
Another approach to investigate the inner retinal
dysfunction of the ganglion cells which may be
altered in glaucoma is by the use of a special mfERG
stimulus to enhance the contributions from the
retinal ganglion cells and the ONHC.63,222,289
Techniques which have been employed to enhance
these components included insertions of three
successive global flashes or alternating dark and
global flashes in between the multifocal stim-
uli.63,222,281 Palmowski et al demonstrated that
patients with POAG had reduction in the nasal
retinal response amplitude to the second of the
three global flashes compared with control.222 The
APPLICATIONS OF MULTIFOCAL ELECTRORETINOGRAPHY
clinical application, however, is limited because
many of the POAG patients still had amplitudes
within normal limits. Fortune et al also showed that
glaucoma patients had less asymmetry between nasal
and temporal responses due to reduction of the
oscillatory component of the induced response in
the temporal retina.63 However, due to the small size
and complex origin of this mfERG oscillatory
component, application of this technique in assess-
ing glaucomatous damage appears to be limited.
OCULAR HYPERTENSION
Chan and Brown reported the use of mfERG in
assessing patients with ocular hypertension (OHT)
who had normal automated perimetry findings.27 It
was found that patients with OHT had significantly
lower first- and second-order kernel response
amplitudes compared with controls. The second-
order kernel response showed larger relative re-
duction compared with first-order response. The
findings suggested that analysis of mfERG especially
the second-order responses may be useful in the
assessment of OHT patients. However, it was unclear
as to the proportion of OHT patients who had
abnormal mfERG and therefore the sensitivity of
mfERG in detecting retinal dysfunction in OHT
patients remained questionable.
LEBER HEREDITARY OPTIC NEUROPATHY
Leber hereditary optic neuropathy (LHON) is
a form of mitochondrial inherited optic atrophy
that causes focal degeneration of retinal ganglion
cells and nerve fiber layers. mfERG recordings with
first- and second-order kernel analyses have been
carried out to investigate the changes in inner
retinal functions of the retinal ganglion cells in
patients with LHON.158 Results demonstrated that
there was loss of a component at around 7.5 msec
after the first-order P1 peak. Second-order kernel
analysis also showed absence of features which
decrease with distance from the fovea which are
present in the control group. These results con-
firmed the presence of inner retinal contribution in
both the first- and second-order mfERG waveforms.
Future Developments of mfERG and
Other Multifocal Techniques
DEVELOPMENTS OF NEW RECORDING
PARAMETERS
By altering the mfERG stimulus parameters,
researchers can use mfERG to investigate various
aspects of retinal electrophysiology at different
retinal locations topographically. The use of eight
87
bright frames followed by eight dark frames allowed
the measurement of multifocal on- and off-re-
sponses.138,144,175 Multifocal OP can also be mea-
sured by using sf-mfERG with insertion of three dark
frames between the multifocal stimuli.11--13,79,317
Responses from ganglion cells and ONHC can also
be enhanced by using alternating dark and global
flashes between the multifocal stimuli.63,281 By
selecting the appropriate emission spectrum of the
color stimulus, specific mfERG responses from L-
and M-cones can be recorded topographi-
cally.4,135,156 This technique of silent substitution
can differentiate protanopes and deuteranopes
from trichromat individuals and has helped in the
understanding of different cone electrophysiologi-
cal activities.4,156 As described previously, apart from
using mfERG for recording responses from the cone
system, rod-mediated mfERG can also be recorded
through dark-adaptation and insertion of dark
frames between the multifocal flashes in order to
study the topographical function of the rod sys-
tem.37,38,55,56,92,93,102
Besides using the conventional m-sequence tech-
nique in the recording of mfERG, the use of an LCD
stimulator has enabled another recording technique
called the cyclic-summation method.168 This method
was found to have better signal-to-noise ratio and
can provide faster recording time compared to the
conventional m-sequence.168 Further study compar-
ing the two recording techniques will be useful in
determining their reliability in the clinical setting.
The conventional CRT and LCD stimulating
systems both have limitations in investigating the
temporal processing mechanism due to restricted
refresh rate duration of 13 msec or more.128 The
development of mfERG system with light-emitting
diodes (LEDs) may enable more rapid stimulation
and has the potential for analysis of temporal
response at a resolution of 1 msec or less.284 This
technique will be useful in assessing the temporal
retinal electrophysiological responses topographi-
cally.
WIDE-FIELD MFERG
WF-mfERG was developed recently and has the
potential to stimulate more peripheral retina
compared with conventional mfERG. Whereas the
testing field of conventional mfERG is around 50--
60 , up to 90 of retina can be stimulated using the
WF-mfERG. As mentioned in previous sections,
studies have demonstrated that WF-mfERG is useful
in the assessment of retinal function in patients with
CRVO,50 retinitis pigmentosa,49 and in the evalua-
tion of vigabatrin-associated retinal toxicity.193,194
However, the system is not readily available at
88 Surv Ophthalmol 52 (1) January--February 2007
present and future commercially available models
should broaden the utilization of this technique.
OTHER MULTIFOCAL TECHNIQUES
Multifocal VEP (mfVEP) is a tool developed for
the objective measurement of cortical response
topographically. The use of mfERG and mfVEP
can differentiate between retinal and optic nerve
diseases as mfERG are normal in visual loss caused
by optic nerve disease alone.103 The applications
and details of the mfVEP are outside the scope of
this review and readers can refer to a review by Hood
et al.100 Gränse et al used mfERG to demonstrate
the macular function is normal in patients with
dominant optic nerve atrophy due to mutation of
OPA1 gene, whereas the mfVEP is abnormal.76
Chen et al has also reported the use of mfERG
and mfVEP in evaluating a patient with papillorenal
syndrome and has confirmed that the visual field
defects were due to retinal ganglion cell and optic
nerve abnormalities rather than outer retinal
dysfunction.39 Studies on the use of mfVEP in
glaucoma also appear to be promising as the mfVEP
defects can reflect the changes in perimetry in-
cluding glaucomatous visual field changes.103,146
Another technique which is based on multifocal
electrophysiology technique is the multifocal pat-
tern ERG (mfPERG). The stimulus is composed of
hexagonal elements each with alternating triangles
and was developed to evaluate ganglion cell
function. MfPERG has been used in the assessment
of chloroquine retinopathy and results showed that
chloroquine maculopathy may cause marked
reduction in mfPERG responses.214 However,
although mfPERG was thought to arise from the
retinal ganglion cells, studies have shown conflicting
results in using mfPERG in the assessment of
glaucoma.136,286 Further research is required in
determining the application of mfPERG in various
ophthalmic disorders.
Conclusions
Since the introduction of mfERG a decade ago,
mfERG has been used in a large variety of clinical
applications. The main strength of mfERG lies in its
ability to provide objective assessment in central
retinal function topographically within a reasonable
short recording time. Through the analysis of
mfERG response amplitudes and implicit times at
different retinal locations, localized areas of retinal
dysfunction caused by acquired or hereditary
diseases can be identified. Application of mfERG is
particularly useful in patients with pathology limited
to the central retina as the full-field ERG in these
LAI ET AL
patients are usually normal. The use of mfERG has
also enabled clinicians to monitor the development
of toxic retinopathy due to systemic therapy and to
objectively monitor the efficacy of surgical and non-
surgical treatment for retinal diseases, as the
changes in retinal function might not be reflected
by subjective measures. The use of different stimulus
and analysis parameters further enhanced the ability
to investigate specific components of retinal elec-
trophysiology topographically. Future developments
and consolidations of the mfERG techniques will
likely broaden the use of mfERG in the clinical
setting.
Method of Literature Search
We conducted a search (January 1980--December
2005) of MEDLINE with the PubMed search engine.
Search words included multifocal electroretinography,
multifocal electroretinogram, multifocal ERG, mERG,
mfERG and mf-ERG. We included all original articles
and case reports that evaluated the clinical applica-
tions of mfERG in various ocular conditions in
human. Further references were retrieved from the
lists of references provided in individual articles.
Publications with duplicated results were excluded.
All articles with English abstract were included and
no distinction was made on the basis of the non-
English languages.
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The authors reported no proprietary or commercial interest in
any product mentioned or concept discussed in this article.
Reprint address: Dr. Timothy Y.Y. Lai, Department of Ophthal-
mology and Visual Sciences, The Chinese University of Hong
Kong, Hong Kong Eye Hospital, 147K Argyle Street, Kowloon,
Hong Kong.